MX2014012991A - Benzamide derivative. - Google Patents

Benzamide derivative.

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Publication number
MX2014012991A
MX2014012991A MX2014012991A MX2014012991A MX2014012991A MX 2014012991 A MX2014012991 A MX 2014012991A MX 2014012991 A MX2014012991 A MX 2014012991A MX 2014012991 A MX2014012991 A MX 2014012991A MX 2014012991 A MX2014012991 A MX 2014012991A
Authority
MX
Mexico
Prior art keywords
carbon atoms
compound
group
chloro
alkyl group
Prior art date
Application number
MX2014012991A
Other languages
Spanish (es)
Inventor
Hiroshi Tanaka
Takeshi Murata
Satoshi Niizuma
Sousuke Hara
Hatsuo Kawada
Kihito Hada
Hideaki Shimada
Yoshito Nakanishi
Original Assignee
Chugai Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd filed Critical Chugai Pharmaceutical Co Ltd
Publication of MX2014012991A publication Critical patent/MX2014012991A/en

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    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
    • C07C321/28—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The present invention pertains to a benzamide derivative represented by formula (I), or a pharmaceutically acceptable salt thereof.

Description

BENZAMIDE DERIVATIVE Field of the Invention The present invention relates to benzamide derivatives or their salts or solvates. More specifically, the present invention relates to benzamide derivatives and provides pharmaceutical products, pharmaceutical compositions and DDR1 inhibitors comprising the compounds, as well as pharmaceuticals comprising the aforementioned compounds, for the treatment of diseases including cancer, metastasis and invasion. carcinogenic, fibrosis and inflammation. The present invention also relates to methods for the treatment of the aforementioned diseases which comprise the administration of effective doses of the compounds or their salts or solvates and the use of the benzamide derivatives for the manufacture of the aforementioned pharmaceutical compositions.
Background of the Invention The Discoidine Domain 1 Receptor (DDR1) is a receptor tyrosine qumase and it is known that DDR1 is activated by collagen as a ligand for signal transduction in cells and the promotion of invasion / metastasis or Survival of cells (Non-Patent Documents 1, 2 and 3). HE considers that DDR1 is an important factor that links the extracellular matrix with the malignant transformation of cancer, since in several types of cancer a high expression and activation of DDR1 is observed.
For example, it is known that clinically high expression of DDR1 is observed in non-small cell lung cancer, glioma, breast cancer and the like (Non-Patent Documents 4, 5, 6 and 7) and it has been reported that High expression is correlated with an unfavorable prognosis in non-small cell lung cancer and glioma. Furthermore, in non-small cell lung cancer and bile duct cancer, the expansion of DDR1 phosphorylation is observed and its activation is strongly suggested (Non-Patent Documents 8 and 9).
Studies that work with RNA interference reveal that DDR1 plays an important role in the bone metastasis of lung cancer cells (Non-Patent Document 5) and contributes to the tumorigenicity of colon cancer or breast cancer as well as of its survival in the presence of agents that damage DNA (Document Not Related to Patent 10). Therefore, compounds that have a DDR1 inhibitory effect are extremely useful for the treatment of cancer.
It has also been reported that the DDR1 ligand, collagen, is abundantly present in tissues fibrosis and that the functions mediated through the activation of DDR1 are involved in several types of fibrosis. For example, the expression of DDR1 appears enhanced in the liver of liver cirrhosis patients (Non-Patent Document 1 1). It has been reported that in the mouse with DDR1 gene deactivation, the formation of fibrils in the kidney induced by the unilateral ureteral ligation is suppressed (Document Not Related to Patent 12) and the formation of fibrils in a model of pulmonary fibrosis induced by bleomycin. it is reduced (Document Not Related to Patent 13). As is clear from the above, the inhibition of DDR1 is extremely useful for the prevention and treatment of organ fibrosis. DDR1 also improves the migration of lymphocytes and the migratory and inflammatory functions of macrophages (Non-Patent Documents 14 and 15). For example, in the mouse with DDR1 gene deactivation, the accumulation of macrophages is suppressed in an arteriosclerosis model (Non-Patent Document 15). It has been reported that in inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis and multiple sclerosis, lymphocytes and macrophages also accumulate and are activated. Therefore, the inhibition of DDR1 is also extremely useful for the prevention and treatment of these diseases caused by inflammation.
Examples of DDR1 inhibitory substances include inhibitors of multicinase which have among their effects the inhibition of DDR1. The reported examples include Gleevec which has a 3-pyridylpyrimidine structure and serves as an inhibitor of bcr-abl, c-kit, CSF1 R, PDGFRa and the like (Patent Document 1, Non-Patent Documents 16 and 17) and Tasigna having a structure of 3-pyridylpyrimidine and serving as an inhibitor of bcr-abl, c-kit, PDGFRα, Lck, Lyn and the like (Patent Document 2, Non-Patent Documents 16 and 17). Other reported examples include Sprycel, which has a structure of 2-methylpyrimidine and serves as an inhibitor of the Src family and the like (Patent Document 3, Non-Patent Documents 16 and 17), I NNO-406 which has a structure of biporimidin-2-ylamino and serves as an inhibitor of bcr-abl, PDGFRa, Lyn, ZAK and the like (Patent Document 4, Document Not Related to Patent 18) and LCB03-01 10 which has a thieno [3,2-b] pyridine structure and serves as an inhibitor of the Src family and the like (Non-Patent Document 19).
However, compounds that selectively inhibit DDR1 are not yet known.
Documents of the Teenica [Non-Patent Documents] [Document Not Related to Patent 1] European Patent No. 564409 specification [Non-Patent Document 2] WO 2004/005281 [Non-Patent Document 3] WO 2004/085388 [Document Not Related to Patent 4] WO 2005/063709 [Non-Patent Document] [Document Not Related to Patent 1] FASEB J. , 13: S77-S82, 1999 [Document Not Related to Patent 2] Mol. Cell, 1: 13-23, 1997 [Document Not Related to Patent 3] Cancer Metastasis Rev, electronic edition, February 26, 2012 [Document Not Related to Patent 4] Oncol. Rep., 24: 31 1 -319, 2010 [Non-Patent Document 5] Clin. Cancer Res., 18: 969-980, 2012 [Document Not Related to Patent 6] Oncogene, 25: 5994-6002, 2006 [Document Not Related to Patent 7] Oncogene, 10: 569-575, 1995 [Document Not Related to Patent 8] Cell, 131: 1 190-1203, 2007 [Document Not Related to Patent 9] PloS One, 6: e15640, 201 1 [Document Not Related to Patent 10] J. Biol. Chem., 286: 17672-17681, 201 1 [Non-Patent Document 1 1] Am. J. Pathol. , 178: 1 134-44, 201 1 [Document Not Related to Patent 12] Am. J. Pathol. , 179: 83-91, 201 1 [Document Not Related to Patent 13] Am. J. Breathe Crit. Care Med., 174: 420-427, 2006 [Document Not Related to Patent 14] FASEB J. , 15: 2724-2726, 2001 [Document Not Related to Patent 15] Circ. Res., 102: 1202-121 1, 2008 [Document Not Related to Patent 16] Blood, 1 10: 4055-4063, 2007 [Non-Patent Document 17] European Journal of Pharmacology, 599: 44-53, 2008 [Document Not Related to Patent 18] Leukemia, 22: 44-50, 2010 [Document Not Related to Patent 19] TH E JOURNAL OF PHAMACOLOGY AND EXPERIM ENTAL THERAPEUTICS, 340: 510-519, 2012 Brief Description of the Invention Problems to be solved by the I nvention An objective of the present invention is to provide low molecular weight compounds that can selectively inhibit the Discoidin 1 Domain Receptor (DDR1) and provide effective pharmaceutical products for diseases linked to DDR1 abnormalities, such as cancer, metastasis and cancerous invasion, fibrosis and inflammation. Means to solve problems Specifically, the present invention comprises: [1 ] A compound represented by the following general formula (I): (I) nta CH2 or NH; represents the following formula (1) or (2): wherein A1 represents N or CR1; R1 represents a halogen atom, cyano group, alkyl group of 1 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms, where the alkyl group of 1 to 3 carbon atoms and the alkoxy group of 1 to 3 atoms of carbon can be substituted with 1 to 5 halogen atoms; R1 can be a hydrogen atom when A2 and / or A3 are A2 represents N or CR2; R2 represents a hydrogen atom, halogen atom, alkyl group of 1 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms, where the alkyl group of 1 to 3 carbon atoms and the alkoxy group of 1 to 3 carbon atoms can be substituted with 1 to 5 carbon atoms halogen; A3 represents N or CR3; R3 represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 3 carbon atoms or an alkoxy group of 1 to 3 carbon atoms, wherein the alkyl group of 1 to 3 carbon atoms and the alkoxy group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms; Y R4 represents an alkylsulfonyl group of 1 to 6 carbon atoms, alkylsulfanyl group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, cycloalkylsulfonyl group of 3 to 8 carbon atoms, cycloalkylsulfanyl group of 3 to 8 atoms carbon, cycloalkylsulphinyl group of 3 to 8 carbon atoms, arylsulfonyl group of 6 to 10 carbon atoms, arylsulfanyl group of 6 to 10 carbon atoms or arylsulfinyl group of 6 to 10 carbon atoms; Y Ring B represents any of the formulas (3) to (9) i i t where B1 represents N or CH; B2 represents N or CR5; R5 represents a halogen atom, alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkenyl group of 2 to 6 carbon atoms, cyano group, nitro group, cycloalkyl group of 3 to 8 atoms carbon, 4- to 10-membered aromatic ring, 4- to 10-membered aromatic heterocycle, 3- to 12-membered heterocycle or alkylsulfanyl group of 1 to 6 carbon atoms, where the alkyl group of 1 to 6 carbon atoms, alkoxy group from 1 to 6 carbon atoms, alkenyl group of 2 to 9 carbon atoms or alkylsulfanyl group of 1 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms; B3 represents N or CR6; B6 represents O, S or NR6; R6 represents a hydrogen atom, the alkyl group of 1 to 3 carbon atoms optionally substituted with a hydroxyl group, halogen atom, amino group, OCOCH3 group or group represented by the following formula (i): · - X- Y- Z (i) where in the formula (i), X represents - (CH2) n-, -NH- or -O-; Y represents a cycloalkyl group of 3 to 8 carbon atoms, aromatic ring of 4 to 10 members, heterocycle of 3 to 12 members, aromatic heterocycle of 4 to 10 members or - (NH (CH2) q) r-, where the group Cycloalkyl of 3 to 8 atoms carbon, 4- to 10-membered aromatic ring, 3- to 12-membered heterocycle or 4- to 10-membered aromatic heterocycle can be substituted with 1 to 5 alkyl groups of 1 to 6 carbon atoms; Z represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, dimethylamine oxide, - (CH2) mN RaRb, -N RiCOC H2RC, - (CH2) mNRiCORc, - (CH2) mORd, - (CH2) mCORe, - (CH2) mNRjS02Rk, - (CH2) mS02Rk, - (CH2) mCON RIRm, cycloalkyl group of 3 to 8 carbon atoms, aromatic heterocycle of 4 to 10 members or heterocycle of 3 to 12 members, where the aromatic heterocycle from 4 to 10 members or from 3 to 12 membered heterocycle can be substituted with 1 to 5 alkyl groups of 1 to 6 carbon atoms; n represents 0, 1, 2 or 3; m represents 0, 1, 2 or 3; q represents 0, 1, 2 or 3; r represents 0, 1, 2 or 3; Ra and Rb are identical or different, each represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, an alkyl group of 2 to 6 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, a heterocycle of 3 to 12 members or -S02GH3, wherein the alkyl group of 1 to 6 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, heterocycle of 3 to 12 members or alkynyl group of 2 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms, hydroxyl groups, alkoxy groups of 1 to 6 carbon atoms, amino groups, -CONH2, mono-alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms, cyano groups, OCH2Ph and / or heterocycle of 3 to 12 members; Re represents an alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, hydroxyl group, cyano group, 3 to 12 membered heterocycle, aromatic heterocycle of 4 to 10 members or amino group, wherein the alkyl group of 1 to 6 carbon atoms can be independently substituted with 1 to 3 hydroxyl, amino, mono-alkylamino of 1 to 6 carbon atoms and / or di-alkylamino of 1 to 6. carbon atoms; Rd represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, wherein the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 3 hydroxyl and / or amino groups; Re represents an alkyl group of 1 to 6 carbon atoms, hydroxyl group, 3 to 12 membered heterocycle or aromatic heterocycle of 4 to 10 members, wherein the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 3 groups hydroxyl and / or amino; Ri represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, where the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms; Rj represents a hydrogen atom or alkyl group of 1 to 6 carbon atoms, where the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms; Rk represents a hydrogen atom, alkyl group of 1 to 6 carbon atoms, amino group, mono-alkylamino group of 1 to 6 carbon atoms or di-alkylamino group of 1 to 6 carbon atoms, wherein the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 3 hydroxyl, amino, mono-alkylamino of 1 to 6 carbon atoms and / or di-alkylamino of 1 to 6 carbon atoms; Y R1 and Rm are identical or different, each represents a hydrogen atom, alkyl group of 1 to 6 carbon atoms or heterocycle of 3 to 12 members, wherein the alkyl group of 1 to 6 carbon atoms can be independently substituted with 1 at 3 amino, mono-alkylamino of 1 to 6 carbon atoms and / or di-alkylamino of 1 to 6 carbon atoms; B4 represents N or CR7; R7 represents a hydrogen atom, halogen atom, cyano group, alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkenyl group of 2 to 6 carbon atoms or cycloalkyl group of 3 to 6 carbon atoms (where the alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkenyl group of 2 to 6 carbon atoms or cycloalkyl group of 3 to 8 carbon atoms can be substituted with 1 to 5 halogen atoms) or a group represented by the following formula (ii): · - X2-Y2-Z2 (i) where X2 represents - (CH2) P-; p represents 0, 1, 2 or 3; Y2 represents a 4- to 10-membered aromatic ring, 3- to 12-membered heterocycle or 4- to 10-membered aromatic heterocycle, where the 4- to 10-membered aromatic ring, 3 to 12 membered heterocycle or 4 to 10 membered aromatic heterocycle it can be substituted with 1 to 5 alkyl groups of 1 to 6 carbon atoms; Z2 represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, hydroxyl group, -NRfRg, 3- to 12-membered heterocycle or 4- to 10-membered aromatic heterocycle, wherein the alkyl group of 1 to 6 carbon atoms it can be substituted with 1 to 5 halogen atoms and the 3- to 12-membered heterocycle or 4- to 10-membered aromatic heterocycle can be substituted with 1 to 5 alkyl groups of 1 to 6 carbon atoms; Y Rf and Rg are identical or different, each represents a hydrogen atom, alkyl group of 1 to 6 carbon atoms, -COCH3 or -S02CH3; B5 represents N or CR8; Y R8 represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or halogen atom, where the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms], a pharmaceutically acceptable salt thereof or its solvate. [2] The compound, a pharmaceutically acceptable salt thereof or its solvate according to [1], wherein the compound is represented by the following general formula (I I): [where Q, Q, R1, R2, R3, R4, R5, R6, B4 and R8 are as defined in [1], respectively]. [3] The compound, a pharmaceutically acceptable salt thereof or its solvate according to [1] or [2], wherein Q is CH2. [4] The compound, a pharmaceutically acceptable salt thereof or solvate according to any one of [1] to [3], wherein R 2 represents a hydrogen atom or alkyl group of 1 to 3 carbon atoms, wherein the alkyl group of 1 to 3 carbon atoms and alkoxy group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms. [5] The compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [4], wherein R3 represents a hydrogen atom, chlorine atom or alkyl group of 1 to 3 carbon atoms, wherein the alkyl group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms. [6] The compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [5], wherein R 5 represents a halogen atom, alkyl group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 atoms of carbon or alkoxy group of 1 to 3 carbon atoms, where the alkyl group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms. [7] The compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [6], where R6 represents a hydrogen atom or a group represented by the following formula (i): · - X-Y-Z (i) where X represents CH2; Y represents piperazine, pyrrolidine, piperidine, morpholine, 3,3-dimethylpiperazine, 3,6-diazabicyclo [3, 1, 1] heptane, azaspiro [2,4] heptane, 2-oxo-1,3-diazinano, 1, 2,5-oxadiazepane, 2-oxopiperidine, azetidine, 5-oxa-2,8-diazaspiro [3,5] nonane, 1,8-diazaspiro [5,5] undecane, imidazole or benzene; Z represents a hydrogen atom, - (CH2) mNRaRb, -NHCOCH Rc, - (CH2) mNHCORc, - (CH2) mORd, - (CH2) mCORe, - (CH2) mCONRIRm, piperazine, pyrrolidine, piperidine or tetrahydropyran; m represents 0, 1, 2 or 3; Ra and Rb are identical or different, each represents a hydrogen atom, alkyl group of 1 to 6 carbon atoms, cycloalkyl group of 3 to 6 carbon atoms or -S02CH3, where the alkyl group of 1 to 6 carbon atoms or cycloalkyl group of 3 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms, hydroxyl groups, alkoxy groups of 1 to 6 carbon atoms, amino groups, -CONH2, mono-alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms or cyano groups; Re represents an alkyl group of 1 to 4 carbon atoms, alkoxy group of 1 to 4 carbon atoms, heterocycle of 4 to 6 members, aromatic heterocycle of 4 to 6 members or amino group, where the alkyl group of 1 to 4 atoms of carbon can be independently substituted with 1 to 2 amino, mono-alkylamino and / or di-alkylamino of 1 to 2 carbon atoms; Rd represents a hydrogen atom or alkyl group of 1 to 2 carbon atoms, where the alkyl group of 1 to 2 carbon atoms can be substituted with an amino group or hydroxyl group; Re represents an alkyl group of 1 to 2 carbon atoms or 4 to 6 membered heterocycle, wherein the alkyl group of 1 to 2 carbon atoms can be substituted with an amino group or hydroxyl group; Y R1 and Rm are identical or different, each represents a hydrogen atom, alkyl group of 1 to 3 carbon atoms or heterocycle of 4 to 6 members, where the alkyl group of 1 to 3 carbon atoms independently substituted with 1 to 3 amino, mono-alkylamino of 1 to 3 carbon atoms and / or di-alkylamino of 1 to 3 carbon atoms. [8] The compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [7], where B4 represents CR7 and R7 represents a chlorine atom, bromine atom, hydrogen atom, cyano group, alkyl group of 1 to 3 carbon atoms, alkoxy group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms, cycloalkyl group from 3 to 6 carbon atoms (wherein the alkyl group of 1 to 3 carbon atoms, alkoxy group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms or cycloalkyl group of 3 to 6 carbon atoms may to be substituted with 1 to 3 halogen atoms) or group represented by the following formula (ii),: · - X2-Y2-Z2 (i i) where X2 represents - (CH2) P-, p represents 0 or 1; Y 2 represents piperazine, pyrrolidine, piperidine, morpholine or 3,3-dimethylpiperazine; Z2 represents a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, -NRfRg, pyrrolidine, morpholine or tetrahydropyran, where the alkyl group of 1 to 3 carbon atoms can be substituted with 1 to 3 halogen atoms; Y Rf and Rg are identical or different, each represents a hydrogen atom, alkyl group of 1 to 3 carbon atoms, -COCH3 or -SO2CH3. [9] The compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [8], wherein R8 represents a hydrogen atom. [10] A pharmaceutical product comprising the compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [9] as an active ingredient. [eleven ] Pharmaceuticals according to [10], where pharmaceutical products are used for the treatment of cancer and / or carcinogenic invasion / metastasis. [12] Pharmaceutical products according to [10], where pharmaceutical products are used for the treatment of fibrosis and / or inflammation. [1 3] A method for the treatment of cancer and / or carcinogenic invasion / metastasis, comprising administering a pharmaceutically effective amount of a composition comprising the compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] a [9] to a patient who needs it. [14] A method for the treatment of fibrosis and / or inflammation, comprising the administration of a pharmaceutically effective amount of a composition comprising the compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [9] ] to a patient who needs it. 15 [15] The use of the compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [9] for the manufacture of an agent for the treatment of cancer and / or carcinogenic invasion / metastasis. 20 [16] The use of the compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [9] for the manufacture of an agent for the treatment of fibrosis and / or inflammation. 25 [1 7] The compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [9] for use in the treatment of cancer and / or carcinogenic invasion / metastasis. [18] The compound, a pharmaceutically acceptable salt thereof or its solvate according to any of [1] to [9] for use in the treatment of fibrosis and / or inflammation.
Effects of the Invention The compounds or their pharmaceutically acceptable salts, or their solvates according to the present invention have an effect of selectively inhibiting the Discoidin 1 Domain Receptor (DDR1). The compounds of the present application may be capable of efficacy for diseases associated with DDR1 abnormalities, such as cancer, cancer invasion and metastasis, fibrosis and inflammation, and may prevent and / or treat diseases for which the above therapeutic agents are not sufficiently effective. Brief Description of the Drawings Fig. 1 is a graph showing an antitumor effect of Compound B-2.
Fig. 2 shows an inhibitory effect of DDR1 phosphorylation of Compound B-2 on tumors.
Mode of Carrying Out the Invention The present invention relates to derivatives of benzamide and its uses. The present inventors for the first time synthesized compounds represented by the formula (I) shown above or their pharmaceutically acceptable salts and found that the compounds or their salts had an inhibitory activity of DDR 1.
Here, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removal of an arbitrary hydrogen atom. It contains no heteroatom or carbon-carbon bond unsaturated in the main chain and has a subset of hydrocarbon or hydrocarbon group structures containing hydrogen and carbon atoms. The alkyl group includes linear and branched structures. Preferred alkyl groups include groups with one to six carbon atoms (C1-6; hereinafter, "Cp_q" means that the number of carbon atoms is paq), alkyl groups of 1 to 5 carbon atoms, alkyl groups of 1 to 4 carbon atoms and alkyl groups of 1 to 3 carbon atoms.
Specifically, alkyl includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, group 2 , 3-dimethylpropyl, 3,3-dimethylbutyl group and hexyl group.
Here, "alkenyl" refers to a monovalent hydrocarbon group having at least one double bond (two adjacent SP2 carbon atoms). The alkenyl group includes linear and branched structures. Depending on the configuration of the double bond and the substituent (if present), the geometry of the double bond can be an entgegen (E) or zuzammen (Z) configuration or a cis or trans configuration. Preferred examples of the alkenyl group include alkenyl groups of 2 to 6 carbon atoms.
Specific examples of alkenyl include a vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group (including cis and trans), 3-butenyl group, pentenyl group and hexenyl group.
Here, "alkyl" refers to a monovalent hydrocarbon group having at least one triple bond (two adjacent SP carbon atoms). The alkynyl group includes linear and branched structures. Preferred examples include alkynyl groups of 2 to 6 carbon atoms.
Specific examples of alkynyl include an ethynyl group, 1-propynyl group, propargyl group, 3-butynyl group, pentynyl group and hexynyl group.
The alkenyl or alkynyl can have one or more double bonds or triple bonds, respectively.
Here, "cycloalkyl" refers to a saturated or partially unsaturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic groups, bicyclo rings and spiro rings. The preferred cycloalkyl includes cycloalkyl groups of 3 to 7 carbon atoms. Specifically, the Cycloalkyl group includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptyl group.
Here, "aryl" refers to a monovalent aromatic hydrocarbon ring. Preferred examples include aryl of 6 to 10 carbon atoms. Specific examples of aryl include a phenyl group and a naphthyl group (e.g., a 1-naphthyl group or 2-naphthyl group).
Here, "halogen atom" refers to a fluorine atom, chlorine atom, bromine atom or iodine atom.
As used herein, "alkoxy" refers to an oxy linked to an "alkyl" defined above. Preferred alkoxy includes alkoxy groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 4 carbon atoms and alkoxy groups of 1 to 3 carbon atoms. Specifically, alkoxy includes, for example, methoxy groups, ethoxy group, 1-propoxy group, 2-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group and ferc-butoxy group.
As used herein, "aromatic ring" refers to a monovalent or aromatic divalent hydrocarbon ring. The aromatic ring may be a single ring or a fused ring. The number of ring-forming atoms is preferably 4 to 10 (aromatic ring of 4 to 10 members).
Specific examples of the aromatic ring include benzene and naphthalene.
In the present, "heterocycle" refers to a heterocycle monovalent or non-aromatic divalent which preferably contains 1 to 5 heteroatoms in ring-forming atoms. The heterocycle may have a double and / or triple bond in the ring, the carbon atoms in the ring may be oxidized to form carbonyl. The heterocycle may be a single ring, fused ring or spiro ring. The number of ring-forming atoms is preferably 3 to 12 (3 to 12 membered heterocycle) and more preferably 4 to 7 (4 to 7 membered heterocycle).
Specific examples of the heterocycle include piperazine, pyrrolidine, piperidine, morpholine, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, tetrahydropyridine, thiomorpholine, pyrazolidine, imidazoline, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, 15 isothiazolidine, thiadiazolidine, azetidine, oxazolidone, benzodioxane, benzoxazoline, dioxolane, 3,6-diazabicyclo [3.1 1] heptane, azaspiro [2.4] heptane, 2-oxo-1, 3-diazinano, 1, 2,5-oxadiazepane, 2-oxopiperidine, azetidine, 5-oxa-2,8-diazaspiro [3.5] nonane and 1,8-diazaspiro [5.5] undecane.
Herein, "aromatic heterocycle" refers to a monovalent or aromatic divalent heterocycle preferably containing 1 to 5 heteroatoms in ring-forming atoms. The aromatic heterocycle can be partially saturated and can be a single ring, fused ring (like a 25 bicyclic aromatic heterocycle in which an aromatic heterocycle monocyclic is fused with a ring of benzene or monocyclic aromatic heterocycle) or spiro ring. The number of ring-forming atoms is preferably 4 to 10 (4 to 10 membered aromatic heterocycle).
Specific examples of the aromatic heterocycle include furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, siathiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzofuran, benzothiophene, benzothiadiazole, benzothiazole, benzoxazole, benzoxadiazole, benzimidazole, indole, isomdol, indazole, qumoline, isoquinoline, cinnoline, quinazoline, quinoxaline, indolizine and imidazopyridine.
In the present, "heteroatom" refers to a nitrogen atom (N), an oxygen atom (O) or a sulfur atom (S).
Here, "monoalkylamino" refers to an amino group to which one of the "alkyl" groups defined above is attached. Preferred examples of monoalkylamino include mono-alkylamino of 1 to 6 carbon atoms.
In the present, "dialkylamino" refers to an amino group linked with two "alkyls" defined above. The two alkyl groups may be the same or different. The dialkylamino preferably includes dialkylamino of 1 to 6 carbon atoms.
As used herein, "alkylsulfonyl" refers to a sulfonyl group linked with an "alkyl" defined above (ie, alkyl-S02-). The alkylsulfonyl preferably includes alkylsulfonyl of 1 to 6 carbon atoms and alkylsulfonyl of 1 to 3 carbon atoms, specifically, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and / -propylsulfonyl.
As used herein, "alkylsulfanyl" refers to a sulfanyl group to which the "alkyl" defined above is attached (ie, alkyl-S-). Preferred examples of the alkylsulfanyl include alkylsulfanyl of 1 to 6 carbon atoms and alkylsulfanyl of 1 to 3 carbon atoms, specifically, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl and / -propylsulfanyl.
As used herein, "alkylsulfinyl" refers to a sulfinyl group to which the "alkyl" defined above is attached (ie, alkyl-SO-). Preferred examples of alkylsulfinyl include alkylsulfinyl of 1 to 6 carbon atoms and alkylsulfinyl of 1 to 3 carbon atoms, specifically, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and / -propylsulfinyl.
As used herein, "arylsulfonyl" refers to a sulfonyl group to which the "aryl" defined above is attached (ie, aryl-S02-). Preferred examples of the arylsulfonyl include arylsulfinyl having 6 to 10 carbon atoms, specifically, phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
As used herein, "arylsulfanyl" refers to a sulfanyl group to which the "aryl" defined above is attached (ie, aryl-S-). Preferred examples of arylsulfanyl include arylsulfanyl of 6 to 10 carbon atoms, specifically, phenylsulfanyl, 1-naphthylsulfanyl and 2-naphthylsulfanyl.
In the present, "arylsulfinyl" refers to a sulfinyl group to which the "aryl" defined above is attached (ie, aryl-SO-). Preferred examples of the arylsulfinyl include arylsulfinyl of 6 to 10 carbon atoms, specifically, phenylsulfinyl, 1-naphthylsulfinyl and 2-naphthylsulfinyl.
As used herein, "cycloalkylsulfonyl" refers to a sulfonyl group to which the "cycloalkyl" defined above is attached (ie, cycloalkyl-S02-). Preferred examples of the cycloalkylsulfonyl include cycloalkylsulfonyl of 3 to 8 carbon atoms, specifically, cyclopentylsulfonyl, cyclohexylsulfonyl and cycloheptylsulfonyl.
As used herein, "cycloalkylsulfanyl" refers to a sulfanyl group to which the "cycloalkyl" defined above is attached (ie, cycloalkyl-S-). Preferred examples of the cycloalkylsulfanyl include cycloalkylsulfanyl having from 3 to 8 carbon atoms, specifically, cyclopentylsulfanyl, cyclohexylsulfonyl, cycloheptylsulfanyl.
As used herein, "cycloalkylsulfinyl" refers to a sulfinyl group to which the "cycloalkyl" defined above is attached (ie, cycloalkyl-SO-). Preferred examples of cycloalkylsulfinyl include cycloalkylsulfinyl of 3 to 8 carbon atoms, specifically, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl.
The compounds of the present invention include free forms and their pharmaceutically acceptable salts. Said "salts" they include, for example, salts of inorganic acid, salts of organic acid, salts of inorganic base, salts of organic base and salts of acidic or basic amino acid.
Preferred inorganic acid salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate and phosphate. Preferred organic salts include, for example, acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, malate, stearate, benzoate, methanesulfonate and p-toluenesulfonate.
Preferred inorganic base salts include, for example, alkali metal salts, such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and ammonium salts. Preferred organic base salts include, for example, diethylamine salts, diethanolamine salts, meglumine salts and N, N-dibenzylethylenediamine salts.
Preferred acidic amino acid salts include, for example, aspartate and glutamate. Preferred amino acid salts include, for example, arginine salts, Usin salts and omitin salts.
When the compounds of the present invention are allowed to stand under the atmosphere, they can absorb moisture to absorb water or form hydrates. Said hydrates are also included in the rooms of the present invention.
Moreover, the compounds of the present invention can absorb other solvents to form solvates. These solvates they are also included in the salts of the present invention.
All structurally possible isomers (geometric isomers, optical isomers, stereoisomers, tautomers, etc.) of the compounds of the present invention and mixtures of said isomers are included in the present invention.
The compounds of the present invention may have polymorphic crystalline forms. Said polymorphic forms are all included in the present invention.
The compounds of the present invention include prodrugs thereof. Prodrugs refer to derivatives of the compounds of the present invention having a chemically or metabolically degradable group and after administration to the living body, returning to the original compounds and exhibiting the efficacy of the original drug. Prodrugs include complexes and non-covalent salts.
The compounds of the present invention include those in which one or more atoms within the molecule have been replaced with isotopes. In the present, the isotope refers to an atom which has the same atomic number (proton number) but is different in mass number (sum of protons and neutrons). The target atoms to be replaced with an isotope in the compounds of the present invention include, for example, hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom and atom. of chlorine. Its isotopes include 2H, 3H, 13C, 14C, 15N, 170, 180, 31P, 32P, 35S, 18F and 36CI. In particular, radioisotopes such as 3H and 14C, which are degraded by emitting radiation, are useful in the study of tissue distribution in vivo, and such pharmaceutical compounds or compounds. The stable isotopes do not decay, they are almost constant in abundance and do not emit radiation. For this reason, stable isotopes can be used safely. The compounds of the present invention can be converted to substituted isotope compounds according to conventional methods by the replacement of reagents used in the synthesis with reagents containing the corresponding isotopes.
Preferably, the compounds of the present invention represented by the formula (I) shown above are the following.
The above Q is preferably CH2.
The above A1 is preferably CR1.
The above R1 preferably is a chlorine atom, bromine atom, fluorine atom, methyl group or cyano group and, more preferably, a chlorine atom.
The above A2 preferably is CR2.
The above R2 is preferably a hydrogen atom.
The above A3 preferably is CR3.
The above R3 preferably is a hydrogen atom, methyl group or chlorine atom.
The above R4 preferably is an alkylsulfonyl group of 2 to 4 carbon atoms, alkylsulfanyl group of 2 to 4 carbon atoms or alkylsulfinyl group of 2 to 4 carbon atoms, more preferably an alkylsulfonyl group of 2 to 4 carbon atoms and even more preferably an ethylsulfonyl group.
The above B1 preferably is CH.
The above B2 preferably is CR5.
Preferably, the above R 5 represents a halogen atom, alkyl group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms, where the alkyl group of 1 to 3 atoms of carbon or alkoxy group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms. More preferably, the above R5 represents a halogen atom, alkyl group of 1 to 3 carbon atoms, alkenyl group of 2 carbon atoms or alkoxy group of 1 carbon atom, where the alkyl group of 1 to 3 carbon atoms or alkoxy group of 1 carbon atom can be substituted with 1 to 3 halogen atoms. The above R 5 is particularly preferably a trifluoromethyl group, trifluoromethoxy group, methyl group, ethyl group, vinyl group, chlorine atom or bromine atom.
The above B3 preferably is CR6.
The above B6 preferably is O or NR6.
Preferably, the above R6 represents a hydrogen atom or a group represented by the following formula (i).
The above X is preferably - (CH2) n-, where n represents 1 or 2 and n preferably is 1.
The above Y preferably represents a 4 to 6 membered heterocycle and is more preferably piperazine, pyrrolidine, piperidine, morpholine, 3,3-dimethylpiperazine, 3,6-diazabicyclo [3.1 1] heptane, azaspiro [2,4] heptane, 2 -oxo-1, 3diazinan, 1, 2,5-oxadiazepane, 2-oxopiperidine, azetidine, 5-oxa-2,8-diazaspiro [3,5] nonane, 1,8-diazaspiro [5,5] undecane, imidazole or benzene. More preferably, the above Y is piperazine, pyrrolidine, piperidine, morpholine or 3,3-dimethylpiperazine.
The above Z preferably is a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, - (CH2) m-NRaRb, -NH COC H2RC, - (CH2) mN HCORc, - (CH2) mORd, - (CH2 ) mCONRIRrn, - (CH2) mORd, - (CH2) mCORe or a heterocyclo of 5 to 6 members, where m represents 0 or 1. The above Z is more preferably a hydrogen atom, - (CH2) m-N RaRb, -NHCOCH2Rc, - (CH2) mNHCORc, -CORe, piperazine, pyrrolidine, piperidine or tetrahydropyran.
Preferably, the above Ra and Rb are identical or different, each represents a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, cycloalkyl group of 4 to 6 carbon atoms, or -S02CH3, where the alkyl group of 1 to 3 carbon atoms or cycloalkyl group of 4 to 6 carbon atoms can be substituted with 1 to 3 halogen atoms, hydrogen atom, amino group, group -CONH2, methylamino, dimethylamino group, cyano group. More preferably, the above Ra and Rb are identical or different, each representing a hydrogen atom, methyl group, ethyl group, isopropyl group, 2-aminoethyl group, 3-aminopropyl group, 2-methyl amino group or -S02CH3.
Preferably, the above Re represents an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 2 carbon atoms, heterocycle of 4 to 6 members, aromatic heterocycle of 4 to 6 members, an amino group, where the group alkyl of 1 to 4 carbon atoms can be substituted independently with 1 or 2 amino, mono-alkylamino of 1 to 2 carbon atoms and / or d-alkylamino of 1 to 2 carbon atoms. More preferably, the above Re represents an alkyl group of 1 to 2 carbon atoms, methoxy group or amino group, where the alkyl group of 1 to 2 carbon atoms can be independently substituted with 1 to 2 amino, mono-alkylamino of 1 to 2 carbon atoms and / or di-alkylamino of 1 to 2 carbon atoms.
Rd is preferably a hydrogen atom or alkyl group of 1 to 2 carbon atoms, wherein the alkyl group of 1 to 2 carbon atoms can be independently substituted with 1 or 2 amino groups or hydroxyl group and, more preferably, a hydrogen atom, methyl group, 2-aminoethyl group or 2-hydroxyethyl group.
Preferably, the above Re represents an alkyl group of 1 to 2 carbon atoms or 4 to 6 membered heterocycle, wherein the alkyl group of 1 to 2 carbon atoms can be substituted with 1 to 3 amino groups. More preferably, the above Re represents an alkyl group of 1 to 2 carbon atoms, wherein the alkyl group of 1 to 2 carbon atoms can be substituted with 1 to 2 amino groups.
The above B4 preferably is CR7.
The above R7 preferably is a hydrogen atom, halogen atom, cyano group, alkyl group of 1 to 3 carbon atoms, alkoxy group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms, cycloalkyl group of 3 to 6 carbon atoms or a group represented by -X2-Y2-Z2, more preferably a hydrogen atom, chlorine atom, bromine atom, cyano group, methyl group, ethyl group, vinyl group, cyclopropyl group or a group represented by -X2-Y2-Z2.
The above X2 preferably is - (CH2) P-, where p represents 0 or 1.
Preferably, the above Y2 represents a 5-6 membered heterocycle, wherein the 5- to 6-membered heterocycle can be substituted with 1 to 5 alkyl groups of 1 to 6 carbon atoms. More preferably, the above Y2 represents piperazine, pyrrolidine, piperidine, morpholine or 3,3-dimethylpiperazine.
Preferably, the above Z2 represents a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, -NRfRg or a 5- to 6-membered heterocycle, wherein the alkyl group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms. More preferably, the above Z2 represents a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, -NRfRg, pyrrolidine, morpholine or tetrahydropyran, where the alkyl group of 1 to 3 carbon atoms can be substituted with 1 to 3 halogen atoms.
Preferably, the above Rf and Rg each represent a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, -COCH3 or -S02CH3.
The above B5 preferably is CR8.
The above R8 preferably is a hydrogen atom or fluorine atom and more preferably a hydrogen atom.
The compounds represented by the formula (I) according to the present invention or their pharmaceutically acceptable salts are useful as compounds having an effect of selectively inhibiting the Discoidin 1 Domain Receptor (DDR1) and are useful for the prevention and / or treatment of cancer, prevention and / or treatment of cancer invasion and metastasis and prevention and / or treatment of fibrosis and inflammation.
Examples of cancer include leukemia (such as acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia), malignant lymphoma (such as Hodgkin's lymphoma and non-Hodgkin's lymphoma), brain tumor, neuroblastoma, glioma, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, cancer vesicle, skin cancer, malignant melanoma, renal cancer, pelvic and ureteral renal cancer, bladder cancer, uterine cancer, testicular cancer and prostate cancer. Preferred examples include non-small cell lung cancer, pancreatic cancer, endometrial cancer, brain tumor, bile duct cancer, colon cancer, breast cancer, ovarian cancer and prostate cancer.
Examples of fibrosis and inflammation include liver fibrosis, renal fibrosis, pulmonary fibrosis, scleroderma / systemic sclerosis, myelofibrosis, endomyocardial fibrosis, hepatitis (non-alcoholic steatohepatitis, alcoholic hepatitis, drug-induced hepatitis, autoimmune hepatitis, and primary biliary cirrhosis), diabetic nephropathy , membranoproliferative glomerulonephritis, focal glomerulosclerosis, IgA nephropathy, membranous nephropathy, L chain deposition disease, lupus nephritis, cryoglobulinemic nephritis, V1H-associated nephritis, purple nephritis, membranoproliferative nephritis, proliferative endocapillary nephritis, mesangial proliferative nephritis, crescent nephritis, nephritis interstitial, hypertensive nephrosclerosis, anti-GBM nephritis (Goodpasture syndrome), HCV, nephropathy linked by HBV, ANCA nephritis, Alport syndrome, chronic pancreatitis, rheumatoid arthritis, atherosclerosis, Crohn's disease, ulcerative colitis and multiple sclerosis.
The compounds of the present invention and their salts can be formulated into tablets, powders, fine granules, granules, capsules of coated tablets, syrups, lozenges, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, drops for the ear, cataplasms, lotions and the like by conventional methods. For the formulation, conventional excipients, binding agents, lubricants, colorants, flavoring agents and, if necessary, stabilizers, emulsifiers, absorbents, surfactants, pH adjusting agents, preservatives, antioxidants and the like can be used. The compounds of the present invention are formulated by the combination of ingredients that are generally used as materials for pharmaceutical preparations, using conventional methods.
For example, to produce oral formulations, the compounds of the present invention or their pharmaceutically acceptable salts are combined with excipients and, if necessary, binding agents, disintegrating agents, lubricants, colorants, flavoring agents and the like; and then formulated into powders, fine granules, granules, tablets, coated tablets, capsules and the like by conventional methods.
The ingredients include, for example, animal oils and vegetables such as soybeans, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalene and solid paraffin; oils of asters, such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as keto stearyl alcohol and behenyl alcohol; silicon resins; silicon oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid polyoxyethylene esters, hydrogenated polyoxyethylene castor oils and polyoxyethylene / polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acids, carboxyvinyl polymers, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyalcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; saccharides such as glucose and sucrose; inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate; and purified water.
The excipients include, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbit, crystalline cellulose and silicon dioxide.
Binders include, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, propylene glycol / polyoxyethylene block polymer and meglumine.
Disintegrating agents include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin and calcium carboxymethylcellulose.
The lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oil.
Approved dyes are used as additives for pharmaceutical products. Flavoring agents used include, for example, cocoa powder, menthol, aromatic powder, mint essence, borneol powder and cinnamon.
Of course, these tablets / granules can be coated with sugar or, if necessary, other appropriate coatings. Alternatively, when producing liquid preparations such as syrups and injections, the compounds of the present invention or their pharmaceutically acceptable salts are combined with pH adjusting agents, solubilizers, isotonization agents or the like and, if necessary, solubilizing agents, stabilizers, and the like, and then formulated with the use of conventional methods.
The methods for producing external preparations are not limited and can be produced by conventional methods. Various conventional materials can be used for pharmaceuticals, quasi-drugs, cosmetics and the like as base materials in the production. Specifically, the base materials used include, for example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicon oils, surfactants, phospholipids, alcohols, polyalcohols, water soluble polymers, minerals of clay and purified water. Moreover, as necessary, pH adjusting agents, antioxidants, chelating agents, preservatives, colorants, flavoring agents and the like can be added. However, the base materials for the external preparations of the present invention are not limited thereto.
Moreover, if necessary, the preparations can be combined with components that have a differentiation induction activity or components such as blood circulation reinforcing agents, antimicrobial agents, antiphlogistic agents, cell activating agents, vitamins, amino acids, humectants and keratolytic agents. . The base materials described above can be added in an amount that provides a concentration normally selected in the production of external preparations.
When administering the compounds of the present invention, their salts or solvates, their dosage forms are not particularly limited and can be administered orally or parenterally by conventionally used methods. They can be formulated and administered as tablets, powders, granules, capsules, syrups, pills, inhalers, suppositories, injections, ointments, eye ointments, eye drops, nose drops, eardrops, poultices, lotions and the like.
The dosage of pharmaceutical products of the present invention may be appropriately selected depending on the severity of the symptoms, age, sex, weight, method of administration, type of salt, specific type of disease and the like.
The dose varies considerably depending on the type of disease, severity of symptoms, age, sex, sensitivity to the agent and the like on the part of the patient. Typically, the agent is administered to an adult once or several times a day at a rate of a daily dose of about 0.03 to 1,000 mg, preferably 0.1 to 500 mg and more preferably 0.1 to 100 mg. When an injection is used, the daily dose is usually about 1 to 3,000 mg / kg, preferably about 3 to 1,000 pg / kg.
When the compounds of the present invention are produced, the material compounds and various reagents can form salts, hydrates or solvates. The type varies depending on the raw material, solvent and the like and is not particularly limited as long as the reactions are not inhibited.
The solvents to be used vary depending on the raw material, reagent and the like, and as a matter of routine, no they are particularly limited as long as they can dissolve the raw materials to a certain extent without inhibiting the reactions.
Various isomers (eg, geometric isomers, optical isomers based on asymmetric carbons, rotational isomers, stereoisomers and tautomers) can be purified and isolated by conventional separation methods such as recrystallization, diastereomer salt methods, enzyme-based resolution methods , various chromatographic methods (for example, thin layer chromatography, column chromatography, high performance liquid chromatography and gas chromatography).
When a compound of the present invention is obtained in a free form, it can be converted by conventional methods into a salt or solvate thereof which can be formed from the compound of the present invention. When a compound of the present invention is obtained as a salt or solvate thereof, it can be converted by conventional methods into a free form of the compound of the present invention.
The compounds of the present invention can be purified / isolated by conventional chemical methods such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various chromatographic methods.
All of the prior art documents cited in this specification are incorporated herein by reference.
The general production methods for the compounds of the present invention and Examples are presented below.
The compounds of the present invention can be synthesized by various methods, some of which are described with reference to the following Reaction Schemes. The Reaction Schemes are illustrative and the present invention is not limited solely to the chemical reactions and conditions explicitly stated. While some substituents may be excluded from the following Reaction Schemes for the sake of clarity, it is not intended with such exclusion to limit the description of the Reaction Schemes. Representative compounds of the present invention can be synthesized using known and appropriate intermediates, compounds and reagents.
The abbreviations used generally in the following production methods and general examples and the names of the reagents and solvents corresponding to the chemical formulas are described below.
AcOH Acetic acid AD mix Asymmetric dihydroxylation mixture AIBN Azobisisobutyronitrile BI NAP 2, 2'-Bis (diphenylphosphino) -1, 1'-binaphthyl Boc f-butoxycarbonyl Boc20 Di-t-bu ti Id i coal ato BOP (Benzotriazol-1-yloxy) - tris (dimethylamino) phosphoniohexafluorophosphate and its derivatives BPO Benzoyl peroxide 9-BBN 9-borabicyclo [3.3.1] nonane CPME Cyclopentyl methyl ether DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene DCE Dichloroethane DCC N, h / '- dicylohexylcarbodiimide DCM Dichloromethane DEAD Diethyl Azodicarboxylate DIPEA N, N- diisopropylethylamine DMF Dimethylformamide DMA Dimethylacetamide DMAP N, A / -Dimethyl-4-aminopyridine DMSO Dimethyl sulfoxide DMT-M M 4- (4,6-Dimethoxy-1, 3,5-triazin-2-yl) -4-methylmorpholinium chloride DPPA Diphenylphosphorylazide Dppf Bis (diphenylphosphino) ferrocene EtOH Ethanol 2-PrOH 2-Propanol EtOAc Ethyl acetate HATU 0- (7-Azabenzotriazole hexafluorophosphate 1 - . 1 - \\) - N, N, N ', L /' - tetramethyluronium HBTU 0- (Benzotriazol-1-yl) hexafluorophosphate N, N, N ', N'-tetramethyluronium HOBT 1 -Hydroxybenzotriazole LDA Diisopropylamide lithium LiHMDS Bis (trimethylsilyl) amide lithium (= Lithium hexamethyldisilazide) m-CPBA m-chloroperbenzoic acid NMP / V-Methylpyrrolidone NBS / V-Bromosuccin i mida NCS A / -Clorosuccinimide N IS / V-yodosuccin i mida nBupAd2 Di (1 -adminyl) -n-butylphosphine MeOH Methanol S-Phos 2-dicyclohexylphosphino-2 ', 6, -dimethoxybiphenyl TBME ferc-butylmethylether TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran WSCDI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride X-Phos 2 ', 4', 6'-Triisopropyl-2- (dicyclohexylphosphino) biphenyl Production Method I Method I is a method for the formation of a backbone of the formula (I I), where Q is CH 2, R 4 is a sulfanyl group or sulfonyl group and R 6 is H or halogen. l - -: 1 1 : '' ! , -: - 1 1 Stage 1-1 Step 1-1 is a step of sulfanylation of a halobenzonitrile derivative 1-a by the formation of a carbon-sulfur bond. This step can be carried out by reacting the halobenzonitrile derivative I-a with an alkylthiol or arylthiol reagent corresponding to PR4 in the presence of a base. The thiol reagent includes acyclic alkylthiols such as methanethiol, ethanethiol, n-propylthiol and / -propylthiol; cyclic alkylthiols such as cyclopentylthiol; and arylthiols such as phenylthiol. The base includes inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate and sodium hydride; and organic bases such as t-BuOK, LDA, LiHMDS, h /, A / -dimethyl-4-aminopyridine and DBU. Potassium carbonate and sodium carbonate. Examples of the solvent include DMF, DMA, DMSO, dichloromethane, THF, acetonitrile, and mixtures thereof. DMF is preferred. The step can also be carried out by reacting the halobenzonitrile derivative I-a with an alkyl / arylthiolate metal corresponding to PR4 under heating in a polar solvent such as DMF as in the method described in WO 2009/131245. Alternatively, the step can also be carried out by reacting the halobenzonitrile derivative with an acyclic alkyl thiol corresponding to 10 PR4 under heating in a polar solvent such as 1,4-dioxane in the presence of a Pd catalyst, Pd catalyst ligand. and base as in the method described in WO 2006/038741. In this case, the Pd catalyst is preferably Pd2 (dba) 3, the Pd catalyst ligand is preferably Xantphos, the base is preferably A /, A / -diisobutylethylamine and the solvent is preferably 1,4-dioxane.
Stage I-2 Step I-2 is a step of reducing a sulfanylbenzonitrile derivative l-b. This step can be carried out by reducing the nitrile group of the sulfanylbenzonitrile derivative l-b by reaction with a reducing agent. The reducing agent includes metal reducing agents such as lithium aluminum hydride, diisobutylaluminum hydride, Selectride, Super-Hydride and sodium borohydride-nickel chloride; and reducing agents of 25 boron as a complete borane-THF and a borane- complex dimethyl sulfide. Lithium aluminum hydride and a borane-THF complex are preferred. The solvent includes THF, dimethylether and dimethoxyethane and is preferably THF.
Stage 1-3 Step 1-3 is a step of sulfanylation of an aldehyde derivative l-d by the formation of a carbon-sulfur bond. This step can be carried out by reaction of the aldehyde derivative l-d with a metal-alkyl / arylthiolate corresponding to PR4 under heating and for example, the method described in WO 2009/131245 can be used as a reference. Examples of metal-alkyl / arylthiolate include sodium ethanethiolate, sodium methanethiolate and potassium ethanethiolate. The solvent includes DMF, DMA, DMSO, dichloromethane, THF, acetonitrile and mixtures thereof and preferably is DMF. The heating is preferably carried out at 50 ° C to 90 ° C. The step can also be carried out by reacting the aldehyde l-d with an alkyl or arylthiol reagent corresponding to PR4 as in the method described in Step 1-1. Alternatively, the step can also be carried out by reacting aldehyde derivative 0d with an acyclic alkylthiol corresponding to PR4 under heating in a polar solvent such as 1,4-dioxane in the presence of a Pd catalyst, Pd ligand catalyst. and base as in the method described in WO 2006/038741. 5 Stage I-4 Step 1-4 is an oximation step of a sulfanylbenzaldehyde derivative l-e. This step can be carried out by reacting the aldehyde I-e with O-methylhydroxylamine hydrochloride in the presence of a base. The base includes pyridine, triethylamine, N, / V-diisobutylethylamine and A /, / V-dimethyl-4-aminopyridine and is preferably pyridine. The solvent used for the reaction includes dichloromethane, THF, acetonitrile and CPME. The solvent should not be used when pyridine is used as the base.
Stage 1-5 Step 1-5 is a step of reducing an O-methyloxime derivative l-f. This step can be carried out by reacting the O-methyloxime derivative l-f with a boron reagent under heating and then treated with an acid. Examples of boron reagent include boron reducing agents such as a borane-TH F complex, a complex of borane-dimethyl sulfide, texilborane and 9-BBN. A borane-THF complex is preferred. Examples of the acid include hydrochloric acid solutions. An aqueous solution of hydrochloric acid is preferred. The solvent includes aprotic solvents and is preferably THF. The heating can be carried out at 50 ° C to 90 ° C.
Stage 1-6 Step 1-6 is a step of converting a sulfanylbenzylamine derivative 1-c into a sulfoxide derivative. This step can be carried out by protecting the free primary amine with a Boc group or the like, converting the derivative into a sulfoxide by oxidation with a peracid such as mCPBA, tBuOOH, H2O2, oxone or potassium permanganate and deprotecting the Boc group by treatment with hydrochloric acid, with reference to the method described in WO 2009/131245. The protecting group is preferably a Boc group and the oxidizing agent preferably is mCPBA. The sulfonylbenzylamine derivative l-g obtained can be isolated as a hydrochloride.
Stage I-7 Step 1-7 is an alkylation step of a sulfonyl chloride derivative l-h. This step can be carried out by converting the sulfonyl chloride derivative l-h to a sulfinate using a reducing agent under in situ heating, and then by alkylation of the sulfinate by treatment with an alkylating agent. The step can be carried out, for example, by the method of B100rg. Med. Chem. 13 (2005) 397-416. The reducing agent for obtaining a sulfinate preferably is sodium sulfite. The alkylating agent includes alkyl halides and 2-halocarboxylic acids and will preferably be alkyl iodides such as ethyl iodide.
Stage I-8 Step I-8 is a bromination step of a sulfonyl toluene derivative l-i (Wohl-Ziegler reaction). This step can be carried out by reacting the sulfonyl toluene derivative l-i with a brominating agent under heating in the presence of a catalytic amount of a radical initiator. The brominating agent includes NBS and / V-bromoimide, preferably, NBS. The radical initiator includes benzoyl peroxide and AI BN and preferably is benzoyl peroxide. The solvent includes carbon tetrachloride, benzene, cyclohexane and acetonitrile and preferably, carbon tetrachloride. The heating temperature is preferably 80 ° C or higher.
Stage 1-9 Step 1-9 is an amination step of a benzyl bromide derivative l-j. This step can be carried out by reacting benzyl bromide I-j with an aminating agent. The aminating agent includes aqueous ammonia, liquid ammonia and ammonia gas and preferably is aqueous ammonia. Examples of the solvent include protic alcohol solvents, water, THF and mixed solvents thereof. Ethanol is preferred.
Stage 1-10 Step 1-10 is a step of sulfanylation to a halobenzene derivative l-k by the formation of a carbon-sulfur bond. This step can be carried out by reacting the halobenzene derivative l-k with a metal-alkyl / arylthiolate corresponding to PR4 under heating and for example, the method described in WO 2009/131245 can be used as a reference. The conditions to be selected in this stage as the reaction reagent and the solvent are the same as those in Stage 1-3.
Stage 1-1 1 Step 1-1 1 is an oxidation step of a sulfanyl toluene derivative l-1 to obtain a sulfoxide. This step can be carried out by reacting the sulfanyl toluene derivative I-1 with an oxidation agent. The oxidizing agent includes peracids such as mCPBA, tBuOOH, H2O2, oxone and potassium permanganate and preferably is two or more equivalents of mCPBA. The solvent includes aprotic solvents and is preferably dichloromethane or ethyl acetate.
Stage 1-12 Step 1-12 is a step of bromination of a sulfonyl toluene derivative I-m (Wohl-Ziegler reaction). This step can be carried out by reacting the sulfonyl toluene derivative I-m with a brominating agent under heating in the presence of a catalytic amount of a radical initiator. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step I-8.
Stage 1-13 Step 1-13 is an amination step of a benzyl bromide derivative l-n. This step can be carried out by reacting the benzyl bromide derivative l-n with an amination agent. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage I-9.
Stage 1-14 Step 1-14 is an amidation step of a sulfanylbenzylamine derivative l-c. This step can be carried out by reacting the sulfanylbenzylamine derivative l-c with a corresponding carboxylic acid in the presence of a condensing agent and a base. A condensation additive may be added as necessary. The condensing agent includes WSCDI, HBTU, HATU, BOP, DCC, DPPA and DMT-MM and is preferably WSCDI, H BTU and HATU. The base includes tertiary amines and preferably is N, / V-diisobutylethylamine. The condensation additive under the above conditions includes HOBT and HOOBT and is preferably HOBT. The solvent includes aprotic solvents and is preferably dichloromethane, TH F, DMF and the like.
Stage 1-15 Step 1-15 is an amidation step of a sulfonylbenzylamine derivative l-g. This step can be carried out by reacting the sulfonylbenzylamine derivative l-g with a corresponding carboxylic acid in the presence of a condensing agent and a base. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Method of production Method I I is a method to form a main chain of formula (I I), where Q is CH2, R4 is a sulfinyl group and R6 is H or halogen.
, Stage 11-1 Step 11-1 is a sulfinylation step of a sulfanyl derivative l-a. This step can be carried out by reacting the sulfanyl derivative I-a with an oxidation agent. The resulting sulfanyl derivative l-b is a racemate. The oxidizing agent includes peracids such as mCPBA, tBuOOH, H2O2, oxone and potassium permanganate and is preferably mCPBA. The preferred amount of the reagent is 0.9 to 1.0 equivalent. The solvent includes aprotic solvents and is preferably dichloromethane or ethyl acetate.
Method of production Method II I is a method for forming a main chain of formula (I I), where Q is NH, R4 is a sulfanyl group or a sulfonyl group and R6 is H. - ' 1 - - I - l . 1 : lll-d lll-e lll-i Stage 111-1 Step 111-1 is a step of dividing the thiazole ring of a benzothiazole derivative I-1-a by hydrolysis. This step can be carried out by hydrolyzing the benzothiazole derivative I-1-a by reaction with an inorganic base under heating. The step can be carried out, for example, by the method of J. Med. Chem. 2002, 45, 2229-2239. The inorganic base includes sodium hydroxide, lithium hydroxide and potassium hydroxide and preferably is sodium hydroxide. The solvent includes ethylene glycol, water, dimethoxyethane and mixed solvents thereof and is preferably a mixed solvent of ethylene glycol and water. The heating is preferably carried out at 100 ° C or higher.
Stage I II-2 Step I I I-2 is an alkylation step of a thiophenol derivative I 1-b. This step can be carried out by reacting the thiophenol derivative I-l-b with an alkylating agent corresponding to PR4 in the presence of a base and a phase transfer catalyst. The alkylating agent includes alkyl iodides, alkyl bromides, alkyl triflates and alkyl mesylates and preferably are alkyl iodides such as ethyl iodide. The base includes inorganic bases such as carbonate potassium, sodium carbonate, cesium carbonate and lithium carbonate; and organic bases such as DBU, t-BuOK, LDA, LiH MDS and N, N-dimethyl-4-aminopyridine. Cesium carbonate, potassium carbonate and DBU are preferred. The phase transfer catalyst includes tetrabutylammonium iodide and tetrabutylammonium bromide. The solvent includes polar aprotic solvents and ether solvents and is preferably DMF or THF.
Stage 111-3 Step 111-3 is a sulphananylation step of a halobenzene derivative I 1-c. This step can be carried out by reacting the halobenzene derivative 11 I-c with a metal alkyl / arylthiolate corresponding to PR4 under heating and, for example, the method described in WO 2009/131245 can be used as a reference. The conditions to be selected in this step, such as the reaction reagent and the solvent, are the same as those in Stage 1-3.
Stage 111-4 Step 111-4 is a step of sulfanylation of a halonitrobenzene derivative ll-d. This step can be carried out by reacting the halonitrobenzene derivative I-1-d with an alkylthiol or arylthiol reagent corresponding to PR4 in the presence of a base. The thiol reagent includes acyclic alkylthiols such as methanethiol, ethanethiol, n-propylthiol and i-propylthiol; cyclic alkylthiols such as cyclopentylthiol; and arylthiols such as phenylthiol. The base includes inorganic bases such as potassium carbonate, carbonate sodium, cesium carbonate, calcium carbonate and sodium hydride; and organic bases such as t-BuOK, LDA, LiHMDS, N, N-dimethyl-4-aminopyridine and DBU. Potassium carbonate and sodium carbonate are preferred. The solvent includes DMF, DMA, DMSO, dichloromethane, THF, acetonitrile and mixtures thereof and preferably is DMF.
Stage 111-5 Step 111-5 is an amination (reduction) step of a sulfanylnitrobenzene derivative l-1-e. This step can be carried out by reacting the sulfanylnitrobenzene derivative I-1-e with a metal agent reducer under acidic conditions. The step can be carried out, for example, with reference to the method described in a patent (EP 1065204). The reducing agent includes iron powder, zinc powder and tin reagents and preferably is iron powder. The acid to be added includes ammonium chloride, acetic acid and hydrochloric acid and preferably is ammonium chloride. The solvent includes protic alcohol solvents, water and mixed solvents thereof and preferably is a mixed solvent of ethanol and water.
Stage 111-6 Step 111 -6 is a step of converting a sulfanil aniline derivative I-1-f into a hydrazine. This step can be carried out by converting the sulfanilanyl derivative I 1 -f to a diazonium salt using a nitrite salt under strongly acidic (Griess reaction) and then the reaction with a metal reducing agent without isolation. The nitrite salt used for conversion to a diazonium salt is preferably sodium nitrite. The metal reducing agent used for the reduction of the diazonium salt in a phenylhydrazine preferably is tin chloride (I I). The solvent includes protic acid solvents and is preferably an aqueous solution of hydrochloric acid.
Stage 111-7 Step 111-7 is an amidation step of a sulfanylphenylhydrazine derivative l-g. This step can be carried out by reacting the sulfanylphenylhydrazine derivative I 1 -g with a corresponding carboxylic acid. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Stage I-8 Step I I-8 is an oxidation step of a sulfanylkethohydrazine derivative 11-1 to obtain a sulfoxide. This step can be carried out by reacting the sulfanylketohydrazine derivative I 1-h with an oxidation agent. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage I-1.
Production Method IV Method IV is a method to form a main chain of formula (I I), where Q represents CH2, R4 represents a sulfonyl group, B4 represents CH and R6 represents X1Y1Z1.
- I - - - I l l II II - - Stage IV-1 Step I V-1 is a step of converting a bromoaniline derivative IV-a into a benzoic acid derivative IV-b in three steps. This step can be carried out by protecting an amino group of the bromoaniline derivative IV-a with a diBoc group under basic conditions and isolation and purification of the protected derivative; Subsequently, the t-butoxycarbonyl group is transferred by treatment with n-butyllithium at -78 ° C; and both the t-Bu group of the ester and the Boc group of amine protecting group are further deprotected under acidic conditions. The stage is carried out with reference to the method of SYNLETT 20 (2005) 3107-3108. Under the diBoc protection conditions, preferably, a catalytic amount of 4-dimethylaminopyridine is added. The solvent includes an aprotic solvent such as a halomethane or ether solvent and is preferably THF. In the transfer of t-butoxycarbonyl, the solvent can be a stable aprotic solvent in a strongly basic condition and preferably is THF. In the deprotection of the t-Bu and Boc groups, the acid includes hydrochloric acid, sulfuric acid, TFA or the like and is preferably TFA and the solvent is preferably dichloromethane.
Stage IV- 2 Step IV-2 is a step of converting the benzoic acid derivative IV-b to a vinylbenzoate IV-c in two steps. This step can be carried out by esterification using an alkylating agent under basic conditions, isolation and purification and the subsequent reaction using a Pd catalyst in the presence of a base and a vinyl agent under heating. The alkylating agent in the esterification includes alkyl halides and will preferably be alkyl iodides. The base includes inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate and sodium hydride; and organic bases such as t-BuOK, LDA, LiHMDS, N, A / -dimethyl-4-aminopyridine and DBU. Potassium carbonate and sodium carbonate are preferred. The solvent includes polar aprotic solvents and ether solvents and is preferably DM F.
Pd catalyst in the vinylation includes zero-valent Pd complexes represented by tetrakistriphenylphosphine palladium. Palladium acetate is preferred using X-Phos or BuPAd2 as a ligand. The vinyl agent includes potassium vinyltrifluoroborate, vinylboronic acid and vinylboronates and is preferably potassium vinyltrifluoroborate. The base is preferably potassium carbonate or cesium carbonate. The solvent is preferably a mixed solvent of toluene and water.
Stage IV-3 Step IV-3 is a step of converting a vinylbenzene derivative IV-c into a benzaldehyde derivative IV-d in two steps. This step can be carried out by dihydroxylation of the vinylbenzene derivative IV-c using an osmium reagent, isolation and purification and subsequent glycol cleavage. The step can be carried out, for example, with reference to the method described in WO 2010/065760. In dihydroxylation, the osmium reagent includes osmium tetroxide, AD mixture or the like and is preferably AD-a mixture or AD-b mixture. The solvent can be a mixed solvent of a solvent soluble in water and water and preferably is a mixed solvent of t-BuOH and water. In the glycol splitting, the oxidizing agent includes sodium metaperiodate, lead tetraacetate or the like and preferably is sodium metaperiodate. The solvent can be a mixed solvent of an organic solvent and water, a solution of acetic acid or the like and is preferably a mixed solvent of TBME and water.
Stage IV-4 Stage IV-4 is a deamination step of an aniline derivative IV-d. This step can be carried out by converting the aniline derivative IV-d into a diazonium salt using a nitrite salt under acidic conditions (Griess reaction) and then reducing without isolation. The nitrite salt used for conversion to a diazonium salt is preferably sodium nitrite. The reducing agent in the reduction of the diazonium salt is preferably formic acid and the formic acid can also be used as a solvent.
Stage IV-5 Step IV-5 is a step of forming a C-N bond from a benzaldehyde derivative IV-e by reductive amination. This step can be carried out by reacting the benzaldehyde derivative IV-e with a primary or secondary amine corresponding to Y1-Z1-Pro in the presence of a reducing agent. The reducing agent includes sodium triacetoxyborohydride, sodium cyanoborohydride and 2-picolino-borane and is preferably sodium triacetoxyborohydride. The solvent includes halomethane solvents and ether solvents and is preferably chloroform, dichloromethane or THF.
Stage IV-6 Step IV-6 is an esterification step of a benzoic acid derivative IV-f. This stage can be done through the reaction of the benzoic acid derivative IV-f with an alkylating agent in the presence of a base. The alkylating agent includes alkyl halides and is preferably alkyl iodides. The base includes inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate and sodium hydride; and organic bases such as t-BuOK, LDA, LiHMDS, N, A / -dimethyl-4-aminopyridine and DBU. Potassium carbonate and sodium carbonate are preferred. The solvent includes polar aprotic solvents and preferably is DMF.
Stage 1V-7 Step IV-7 is a step of brominating a benzoate derivative IV-g (Wohl-Ziegler reaction). This step can be carried out by reacting the benzoate derivative IV-g with a brominating agent under heating in the presence of a catalytic amount of a radical initiator. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-8.
Stage IV-8 Step IV-8 is a step of forming a C-N bond from a benzyl bromide derivative IV-h by a substitution reaction. This step can be carried out by reacting the benzyl bromide derivative IV-h with a primary or secondary amine corresponding to Y1-Z1-Pro in the presence of a base. The base includes inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, carbonate calcium and sodium hydride; and organic bases such as pyridine, triethylamine, N, A / -diisobutileti sheet, N, A / -dimethyl-4-aminopyridine, t-BuOK, LDA, LiHM DS, N, A / -dimethyl-4-aminopyridine and DBU. Triethylamine and potassium carbonate are preferred. The solvent includes halomethane solvents, ether solvents and polar aprotic solvents and is preferably dichloromethane, THF and DMF.
Stage IV-9 Stage IV-9 is an esterification step of a benzoic acid derivative IV-j. This step can be carried out by reacting the benzoic acid derivative IV-j with an alkylating agent in the presence of a base. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-6.
Stage IV-10 Step IV-10 is a step of forming a C-C bond from a halobenzoate derivative IV-k through a Suzuki-Molander coupling reaction. This step can be carried out by reacting the halobenzoate derivative IV-k with a Molander reagent (potassium trifluoroborate derivative) corresponding to CH2-Y1-Z1-Pro under heating in the presence of a palladium and base reagent. In this case, a reagent for the palladium ligands is added as necessary. The step can be carried out, for example, by the method of Acc. Chem. Res. 2007, 40, 275-286. Examples of the Pd reagent typically include palladium acetate, tetrakistriphenylphosphine palladium and dichloride-dichloromethane complex of 1,1'-bis (d-phenylphosphino) ferrocene-palladium (11). Palladium acetate is preferred. The reagent for palladium ligands includes X-Phos, S-Phos, triphenylphosphine and tricyclohexylphosphine and is preferably X-Phos, S-Phos and nBuPAd2. The base includes inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate and tripotassium phosphate; and organic amines such as triethylamine, t-butylamine, N, A / -diisobutylethylamine and pyridine. Potassium carbonate and cesium carbonate are preferred. The solvent includes alcohols, toluene, THF and mixed solvents of these solvents and water and preferably is a mixed THF solvent and water, toluene or a mixed solvent of toluene and water.
Stage I V-1 1 Stage IV-1 1 is a saponification step (hydrolyzation) of a benzoate derivative IV-i. This step can be carried out by reacting the benzoate derivative IV-i with an inorganic base. Examples of inorganic base include sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide. Sodium hydroxide and potassium hydroxide are preferred. The solvent includes alcohols, water and mixed solvents thereof and preferably is an aqueous solution of ethanol or an aqueous solution of methanol. When the reaction is slow, the reaction can be carried out under heating at 40 ° C to 60 ° C.
Stage IV-12 Stage IV-12 is a step of condensation (amidation) to a benzoic acid derivative IV-I. This step can be carried out by reacting the benzoic acid derivative IV-I with a corresponding benzylamine l-g derivative in the presence of a condensing agent and a base. A condensation aid may be added as necessary. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Stage IV-13 Step IV-13 is a step of dibroming a toluene derivative IV-n (Wohl-Ziegler reaction). This step can be carried out by reacting the toluene derivative IV-n with a brominating agent under heating in the presence of a catalytic amount of a radical initiator. The brominating agent includes NBS and / V-bromoimide and preferably is two or more equivalents of N BS. The radical initiator includes benzoyl peroxide and AI BN and preferably is benzoyl peroxide. The solvent includes carbon tetrachloride, benzene, cyclohexane and acetonitrile and is preferably carbon tetrachloride. The heating temperature is preferably 80 ° C or higher and can be carried out under reflux.
Stage IV-14 Step IV-14 is a step of converting a dibromotoluene derivative IV-o into an aldehyde. This step can be carried out by the reaction of the dibromotoluene derivative IV-o with silver nitrate under heating. The step can be performed, for example, by the method of J. Chem. Soc. (1939) 781. The solvent includes water, water soluble solvents and mixed solvents thereof and is preferably an aqueous solution of acetone. The heating temperature is preferably 60 ° C.
Stage IV-15 Step IV-15 is a condensation (amidation) step of a benzaldehyde derivative IV-p. This step can be carried out by reacting the benzaldehyde derivative IV-p with a corresponding l-g benzylamine derivative in the presence of a base. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Stage IV-16 Step IV-16 is a deprotection step of an amine protecting group of a protected amine derivative IV-m. In this case, the protecting group refers mainly to a Boc group. This step can be carried out by the reaction of the protected amine derivative IV-m under strongly acidic conditions. The acid includes TFA, hydrochloric acid, sulfuric acid, mesyl acid and Lewis acids and is preferably TFA or hydrochloric acid. The solvent includes dichloromethane, ethyl acetate, 1,4-dioxane, acetonitrile, water and mixed solvents thereof and preferably is dichloromethane, ethyl acetate or 1,4-dioxane.
Production Method V Method V is a method for forming a backbone of formula (II), where Q represents CH2, R4 represents a sulfonyl group, B4 represents CR7, R6 represents X1Y1Z1 and R7 represents halogen. l l - - l - - l l - 1 - - - l l - l l -. - l | - l l ' - l l - Step V-1 is a step of halogenation of a benzaldehyde derivative IV-d. This step can be carried out by reacting the benzaldehyde derivative IV-d with a halogenating agent under heating. An acid or a catalytic amount of a radical initiator can be added when the reaction proceeds slowly. The halogenating agent includes / V-halosuccinimides, sulfuryl halides and chlorine, bromide and iodide under acidic conditions or in the presence of reduced iron powder and preferably is / V-halosuccinimides. The solvent includes polar aprotic solvents, halomethane solvents, ether solvents, alcohols and water and preferably is DMF. Stage V-2 Step V-2 is a deamination step of an aniline derivative V-a. This step can be carried out by converting the aniline derivative V-a into a diazonium salt using a nitrite salt under acidic conditions (Griess reaction) and then reducing it without isolation. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-4.
Stage V-3 Step V-3 is a saponification step (hydrolyzation) of a benzoate derivative V-b. This step can be carried out by reacting the benzoate derivative V-b with an inorganic base. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-1 1.
Stage V-4 Step V-4 is a condensation (amidation) step of a benzoic acid derivative V-c. This step can be carried out by reacting the benzoic acid derivative V-c with a corresponding benzylamine derivative l-g in the presence of a condensation agent and a base. A condensation additive may be added as necessary. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Stage V-5 Step V-5 is a step of forming a C-N bond from a benzaldehyde derivative V-d through reductive amination. This step can be carried out by reacting the benzaldehyde derivative V-d with a primary or secondary amine corresponding to Y1-Z1-Pro in the presence of a reducing agent. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-5.
Stage V-6 Step V-6 is a step of forming a C-C bond of a halobenzoate derivative V-f by Suzuki-Molander coupling reaction. This step can be carried out by reacting the halobenzoate derivative V-f with a Molander reagent (potassium trifluoroborate derivative) corresponding to CH2-Y1-Z1-Pro under heating in the presence of a palladium and base reagent. In this case, a reagent for palladium ligands is added as necessary. The step can be carried out, for example, by the method of Acc. Chem. Res. 2007, 40, 275-286. The conditions to be selected at this stage as the reaction reagent and the solvent are the same as those in Stage IV-10. Stage V-7 Step V-7 is a step of halogenation of a benzoate derivative V-g. This step can be carried out by reacting the benzoate derivative V-g with a halogenating agent. The heating can be carried out or an acid or a catalytic amount of a radical initiator can be added when the reaction proceeds slowly. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step V-1.
Stage V-8 Step V-8 is a deamination step of an aniline derivative V-h. This step can be carried out by converting the aniline derivative V-h into a diazonium salt using a nitrite salt under acidic conditions (Griess reaction) and then reducing it without isolation. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-4.
Stage V-9 Step V-9 is a saponification step (hydrolyzation) of a benzoate derivative V-i. This step can be carried out by reaction of the benzoate derivative V-i with an inorganic base. The conditions to be selected in this stage as the reaction reagent and the solvent are the same as those in Stage I V- 1 1.
Stage V-10 Step V-10 is a condensation (amidation) step of a benzoic acid derivative V-j. This step can be carried out by reacting the benzoic acid derivative V-j with a corresponding l-g benzylamine derivative in the presence of a condensing agent and a base. A condensation additive may be added as necessary. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Stage V-1 1 Step V-1 is a step of a benzoic acid conversion derivative V-k by halogenation and esterification. The halogenation step can be carried out by reaction of the benzoic acid derivative V-k with a halogenation agent. The heating can be carried out or an acid or a catalytic amount of a radical initiator can be added when the reaction proceeds slowly. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step V-1. The esterification step can be carried out by reacting the halobenzoic acid derivative obtained in the above halogenation step with an alcohol corresponding to Alk by heating under acidic conditions. The alcohol includes lower alcohols and preferably is methanol. The acid includes inorganic acids and preferably it is sulfuric acid.
Stage V-12 Step V-12 is a step of iodinating an aniline derivative V-1. This step can be carried out by converting an aniline derivative V-1 into a diazonium salt using a nitrite salt under acidic conditions (Griess reaction) and then reacting with an uninsulated metal iodide (Sandmcyer reaction). The nitrite salt used for conversion to a diazonium salt is preferably sodium nitrite. The acid includes sulfuric acid, hydrochloric acid and mesylic acid and is preferably sulfuric acid. In this case, the solvent includes polar solvents such as trifluoroethanol, DMF and acetonitrile and is preferably trifluoroethanol. The metal iodide includes potassium iodide, sodium iodide and lithium iodide and is preferably potassium iodide.
Stage V-13 Step V-13 is a step of converting an iodobenzene derivative V-m by formylation and reduction. This step can be carried out by converting the iodobenzene derivative V-m to a benzaldehyde derivative through metallization using an organometallic reagent and the subsequent reaction with a formylating agent; and then its reaction with a hydride reducing agent without isolation. The metallizing agent includes Grignard reagents and other alkyl metals and is preferably isopropylmagnesium bromide. He Formulating agent includes AM-morpholine, DM F, methyl formate and A / -methyl- / V-pyridin-2-ylformamide and preferably is / V-formylmorpholine. The hydride reducing agent includes sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium triacetoxyborohydride and Selectride and preferably is sodium borohydride. The solvent includes ether solvents and aromatic solvents and is preferably TH F.
Stage V-14 Step V-14 is a saponification (hydrolyzing) step of a benzoate derivative V-n. This step can be carried out by reacting the benzoate derivative V-n with an inorganic base. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-1 1.
Stage V-15 Step V-15 is a condensation (amidation) step of a benzoic acid derivative V-o. This step can be carried out by reacting the benzoic acid derivative V-o with a corresponding benzylamine derivative l-g in the presence of a condensing agent and a base. A condensation additive may be added as necessary. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Stage V-16 Step V-16 is a step of introducing a leaving group into a benzyl alcohol derivative V-p (halogenation or sulfonation). This step can be carried out by reacting the benzyl alcohol derivative V-p with a halogenation reagent or a sulfonating reagent. Halogenation using a halogenation reagent is preferably bromination using carbon tetrabromide, / V-bromosuccinimide, dibromoisocyanuric acid or the like and more preferably reaction with carbon tetrabromide in the presence of triphenylphosphine. Sulfonation using a sulfonating reagent includes methanesulfonylation, p-toluenesulfonylation or triflation and is preferably methanesulfonylation by reaction with methanesulfonyl chloride in the presence of a tertiary amine. Stage V-17 Step V-17 is a step of substitution reaction of an amide derivative V-q. This step can be carried out by reacting the amide derivative V-q with a primary or secondary amine corresponding to Y1-Z1-Pro. Preferred examples of the solvent include polar aprotic solvents, ether solvents and halomethane solvents. The most preferred option is DM F. It is preferred to add an inorganic salt such as potassium carbonate or sodium carbonate or heat at 40 ° C to 80 ° C when the reaction is slow.
Stage V-18 Stage V-18 is a phase of deprotection of the group amine protector of a protected amine derivative V-e. In this case, the protecting group refers mainly to a Boc group. This step can be carried out by the reaction of the protected amine derivative V-e under strongly acidic conditions. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-16.
Production Method VI Method VI is a method to form a main chain of formula (I I), where Q represents CH 2, R 4 represents a sulfonyl group, B 4 represents CR 7, R 6 represents H and R 7 represents X 2 Y 2 Z 2. l I .
Stage VI-1 Step VI-1 is an esterification step of a benzoic acid derivative Vl-a. This step can be carried out by reacting the benzoic acid derivative Vl-a with an alkylating agent in the presence of a base. The conditions to be selected at this stage as the reaction reagent and the solvent are the same as those in Stage IV-6.
Stage VI-2 Step VI-2 is a step of forming a C-N bond of a haloaryl derivative Vl-b by the Buchwald-Hartwig reaction. This step can be carried out by reacting the haloaryl derivative Vl-b with a secondary amine corresponding to Y2-Z2-Pro under heating in the presence of a palladium catalyst, reagent for palladium ligands and base. The step can be carried out, for example, by the method of Organic Synthesis, Coll. Vol. 10, p. 423 (2004); Vol. 78, p. 23 (2002) or Synlett 2006 (9): 1283. The palladium catalyst includes several palladium catalysts such as tris (dibenzylidene ketone) dipalladium (0), palladium acetate and (Pd [P (o-Tolyl) 3] 2) and preferably it is tris (dibenzylideneacetone) dipalladium (0). The reagent for palladium ligands includes various reagents for palladium ligands such as BI NAP, dppf, Xantophos and tri (t-butyl) phosphine and is preferably BI NAP. The base includes potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium ferc-butoxide, and sodium ferc-butoxide and preferably it is cesium carbonate. The solvent is preferably toluene.
Stage VI-3 Step VI-3 is a saponification step (hydrolyzation) of a benzoate derivative Vl-c. This step can be carried out by reacting the benzoate derivative Vl-c with an inorganic base. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-1 1.
Stage VI-4 Step VI-4 is a condensation (amidation) step of a benzoic acid derivative Vl-d. This step can be carried out by reacting the benzoic acid derivative Vl-d with a corresponding l-g benzylamine derivative in the presence of a condensing agent and a base. A condensation additive may be added as necessary. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Stage VI-5 Step VI-5 is a deprotection step of the amine protecting group of a protected amine derivative Vl-e. In this case, the protecting group refers mainly to a Boc group. This step can be carried out by the reaction of the protected amine derivative Vl-e under strongly acidic conditions. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Stage IV-16.
Stage VI-6 Stage VI-6 is a stage of condensation (amidation) of the Benzoic acid derivative Vl-a. This step can be carried out by reacting the benzoic acid derivative Vl-a with a corresponding l-g benzylamine derivative in the presence of a condensing agent and a base. A condensation additive may be added as necessary. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step 1-14.
Stage VI-7 Step VI-7 is a step of forming a C-N bond of a haloaryl derivative Vl-g by Buchwald-Hartwig reaction. This step can be carried out by reacting the haloaryl derivative Vl-g with a secondary amine corresponding to Y2-Z2-Pro under heating in the presence of a palladium catalyst, a reagent for the palladium and base ligands. The step can be carried out, for example, by the method of Organic Synthesis, Coll. Vol. 10, p. 423 (2004); Vol. 78, p. 23 (2002) or Synlett 2006 (9): 1283. The conditions to be selected in this step as the reaction reagent and the solvent are the same as those in Step VI-2. Examples Herein, the present invention is specifically described with reference to the Examples, but should not be construed as limiting them.
NMR analysis The NMR analysis was performed with ARX 300 (300 M Hz) manufactured by Bruker Corporation, AVANCE I I600 (600 MHz) manufactured by Bruker Corporation, J NM-GSX 400 (400 MHz) manufactured by JEOL Corporation, J NM-EX 270 (270 MHz) manufactured by JEOL Corporation, ECA-400 (400 MHz) manufactured by JEOL Corporation or 400MR (400 MHz) manufactured by Varian Corporation. The NMR data are reported in ppm (parts per million) (6) and in reference to the deuterium closure signal of the sample solvent.
Mass spectrometry data of high performance liquid chromatography (LC-MS) Data was obtained using a Micromass SQD Mass Spectrometer in conjunction with Acquity Gradient Ultra High Performance Liquid Chromatography (manufactured by Waters Corporation), SQD2 Mass Spectrometer in conjunction with an Acquity Ultra High Performance Liquid Chromatography Acquity (manufactured by Waters Corporation), a device Micromass ZQ Mass Spectrometer in conjunction with 2525 Gradient High Performance Liquid Chromatography (manufactured by Waters Corporation) or Micromass SQD Mass Spectrometer in conjunction with 2524 Gradient High Performance Liquid Chromatography (manufactured by Waters Corporation).
Any of the conditions in the following Table 1 has been used for high performance liquid chromatography. [Table 1 ] Microwave reaction The reaction was carried out in a Biotage Initiator using reaction vials with a lid under pressure. The maximum flow configuration includes air cooling of the reaction vessel to prevent a rise in temperature due to microwave radiation.
Commercially available reagents were used without further purification. Ambient temperature refers to temperature within the range of approximately 20-25 ° C.
All non-aqueous reactions were carried out in anhydrous solvents. Concentration was performed under reduced pressure or evaporation of solvent using a rotary evaporator. In the HPLC fractionation, after a target material was isolated, the material was obtained as a free form by carrying out the neutralization as necessary.
In the preparation of a compound, when there was the possibility of an undesirable collateral reaction, a functional group was protected by a protecting group as necessary and the protecting group was removed after preparing the target molecule. The selection and removal of the protecting group was performed using, for example, a method described in Greene and Wuts, "Protective Groups in Organic Synthesis" (Fourth Edition, John Wilcy &Sons 2007).
[Example 1 ] Compound a1 5-chloro-2-ethylsulfanyl-benzonitrile A solution of 5-chloro-2-fluoro-benzonitrile (3.60 g, 23.1 mmol) in DMF (46 mL) was cooled to 0 ° C. Potassium carbonate (9.60 g, 69.4 mmol) was added under a nitrogen atmosphere and the mixture was stirred at room temperature for five minutes. Ethanethiol (2.05 ml, 27.8 mmol) was added and the mixture was stirred at room temperature for three hours. Ethyl acetate was added to the reaction mixture. After washing with saturated saline, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (4.57 g, quant.) As a colorless solid.
HPLC retention time: 2.47 min (analysis condition D) 1 H-NMR (400 MHz, DMSO) d: 8.01 (1 H, d, J = 2.2 Hz), 7.73 (1 H, dd, J = 2.2, 8.8 Hz), 7.58 (1 H, d, J = 8.8 Hz), 3.14 (2H, q, J = 7.7 Hz), 1.27 (t, J = 7.7 Hz).
[Example 2] Compound a2 5-chloro-2-ethylosulfanyl-benzylamine Lithium aluminum hydride (2.63 g, 69.4 mmol) was added to a solution of 5-chloro-2-ethylsulfanyl-benzonitrile (Compound 1, 4.57 g, 23.1 mmol) in TH F (40 mL) while cooling to 0 ° C. The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for one hour. Water was added to the reaction mixture while cooling to 0 ° C, followed by filtration through celite. The filtrate was dried over anhydrous magnesium sulfate and the drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.00 g, 85%) as a yellow oily substance.
LCMS: m / z 202 [M + H] + HPLC retention time: 0.97 min (analysis condition D) [Example 3] Compound A-1 3-bromo-N- (5-chloro-2-ethylsulfanyl-benzyl) -5-trifluoromethyl-benzamide HOBT (35.2 mg, 0.23 mmol) was added to a suspension of 5-chloro-2-ethylsulfanyl-benzylamine (Compound a2, 37.8 mg, 0.19 mmol), 3-bromo-5- (trifluoromethyl) -benzoic acid (19.9 mg, 0.20 mmol) and WSCDI (43.1 mg, 0.23 mmol) in DCM (2 ml), followed by agitation for 20 hours. DCM was added to the reaction mixture. After washing with water, the organic layer was dried with anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (78.0 mg, 92%) as a colorless solid.
LCMS: m / z 452 [M + H] + HPLC retention time: 1, 06 min (analysis condition A) [Example 4] Compound A-2 3-bromo-N- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide M-CPBA (85.8 mg, 0.50 mmol) was added to a solution of 3-bromo-N- (5-c lo ro-2-ethylsulfa nyl-benzyl) -5-tri-fluo-romethyl-benzamide (Compound A-1, 72.8 mg, 0.16 mmol) in DCM (2.5 ml), followed by stirring for 20 hours. DCM was added to the reaction mixture. After washing with water, the organic layer was dried with anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by column chromatography on silica gel of amine (ethyl acetate / hexane) to give the title compound (69.6 mg, 89%) as a colorless solid.
LCMS: m / z 484 [M + H] + HPLC retention time: 0.94 min (analysis condition A) [Example 5] Compound A-3 3-chloro-N- (5-chloro-2-ethylsulfanyl-benzyl) -5-trifluoromethoxy-benzamide Synthesis of the title compound was carried out from 5-chloro-2-ethylsulfanyl-benzylamine (Compound a2) and 3-chloro-5-trifluoromethoxy-benzoic acid under the same conditions as for Compound A-1.
LCMS: m / z 424 [M + H] + HPLC retention time: 1.06 min (analysis condition A) [Example 6] Compound A-4 3-chloro-N- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide Synthesis of the title compound was carried out from 3-chloro-N- (5-chloro-2-ethylsulfanyl-benzyl) -5-trifluoromethoxy-benzamide (Compound A-3) under the same conditions as for Compound A- 2.
LCMS: m / z 456 [M + H] + HPLC retention time: 0.94 min (analysis condition A) [Example 7] Compound a3 5-Chloro-2-ethanesulfonyl-benzylamine hydrochloride Compound a3 was synthesized from 5-chloro-2-ethylsulfanyl-benzylamine (Compound a2) according to the method described in WO 2009131245.
[Example 8] Compound A-5 / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide DI PEA (0.016 ml, 0.091 mmol) was added to a suspension of 5-chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3, 20.5 mg, 0.076 mmol), 3- (trifluoromethyl) -benzoic acid (18.0 mg , 0.095 mmol) and WSCDI (18.9 mg, 0.099 mmol) in DCM (1.5 mi), followed by stirring for 20 hours. DCM was added to the reaction mixture. After washing with water, the organic layer was dried with anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (26.9 mg, 87%) in the form of a colorless solid.
LCMS: m / z 406 [M + H] + HPLC retention time: 0.83 min (analysis condition A) [Examples 9 to 18] The compounds of Table 2 were then synthesized from the corresponding carboxylic acids under the same conditions as for Compound A-5. However, DMF was used as a solvent in the synthesis of Compound A-10. [Table 2] [Example 19] Compound A-14 4-bromo-N- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide DIPEA (1.90 ml, 11 mmol) was added to a solution of 5-chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3, 1.00 g, 3.7 mmol), 4-bromo-3-trifluoromethylbenzoic acid ( 1.1 g, 4.1 mmol), WSCDI (1.06 g, 5.6 mmol) and HOBT (0.75 g, 5.6 mmol) in DMF (18.5 mL); and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate; and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / DCM / hexane) to yield the title compound (1.56 g, 87%) as a colorless solid.
LCMS: m / z 484 [M + H] + HPLC retention time: 0.92 min (analysis condition A) [Example 20] Compound a4 2 til lf nyl-5-fluoro-phenylamine added ethyl iodide (0.66 ml, 8.3 mmol) to a pn of 2-amino-4-fluoro-benzenethiol (1.13 g, 7.9 mmol), cesium carbonate (3.09 g, 9.5 mmol) and tetra-n-butylammonium iodide (3.21 g, 8.7 mmol) in DMF (10%). mi) under a nitrogen atmosphere, followed by stirring for 2.5 hours. Ethyl acetate was added to the reaction mixture. After washing with a saturated aqueous solution of sodium chloride. sodium, the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (1.19 g, 88%). as a colorless oily substance.
LCMS: m / z 172 [M + H] + HPLC retention time: 2.35 min (condition of analysis D) [Example 21] Compound a5 (2-ethylsulfanyl-5-fluoro-pheny1) -hydrazine Concentrated hydrochloric acid (1.8 ml) and sodium nitrite (145 mg, 2.1 mmol) were added to a suspension of 2-ethylsulfanyl-5-fluoro-phenylamine (Compound a4, 300 mg, 1.8 mmol) in water ( 1.8 m) and the mixture was stirred for two hours under cooling with ice. A solution of stannic chloride dihydrate (909 mg, 4.0 mmol) in concentrated hydrochloric acid (1.8 ml) was added to this reaction solution and the mixture was stirred for one hour under ice-cooling. An aqueous solution of 5N sodium hydroxide (9 ml) was added, followed by extraction with DCM. The extract was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to yield the title compound (299 mg, 91%) as a pink oily substance.
HPLC retention time: 0.51 min (analysis condition A) 1 H-NMR (400 MHz, CDCl 3) d: 7.33 (1 H, dd, J = 8.2, 6.6 Hz), 6.79 (1 H, dd, J = 11.0, 2.7 Hz), 6.48 (1 H, s), 6.40 (1H, td, J = 8. 2, 2.7 Hz), 3.58 (2H, brs), 2.65 (2H, q, J = 7.3 Hz), 1.17 (3H, t, J = 7.3 Hz).
[Example 22] Compound A-17 / \ /, - (2-ethylsulfanyl-5-fluoro-phenyl-hydrazide of 3-trifluoridene-benzoic acid) Synthesis of the title compound was carried out from (2-ethylsulfanyl-5-fluoro-phenyl) -hydrazine (Compound a5) and 3-trifluoromethylbenzoic acid under the same conditions as for Compound A-1.
LCMS: m / z 359 [M + H] + HPLC retention time: 0.93 min (analysis condition A) [Example 23] Compound A-18 / V '- (2-ethanesulfonyl-5-fluoro-phenyl) -hydrazide of 3-trifluoro methyl benzoic acid Synthesis of the title compound was carried out from N '- (2-ethylsulfanyl-5-fluoro-phenyl) -hydrazide of 3-trifluoromethylbenzoic acid (Compound A-17) under the same conditions as for Compound A-2.
LCMS: m / z 391 [M + H] + H PLC retention time: 0.82 min (analysis condition A) [Example 24] Compound A-19 N- (2-ethylsulfanyl-5-fluoro-benzyl) -3-trifluoromethyl-benzamide The title compound was synthesized from 2,5-difluoro-benzonitrile under the same conditions as for Compounds a1, a2 and A-1. However, the reaction was performed using 3-trifluoromethylbenzoic acid in place of 3-bromo-5- (trifluoromethyl) -benzoic acid under the conditions as for Compound A-1.
LCMS: m / z 358 [M + H] + H PLC retention time: 0.95 min (analysis condition A) [Example 25] Compound A-20 N- (2-ethanesulfonyl-5-fluoro-benzyl) -3-trifluoromethyl-benzamide Synthesis of the title compound was carried out from N- (2-ethylsulfanyl-5-fluoro-benzyl) -3-trifluoromethyl-benzamide (Compound A-19) under the same conditions as for Compound A-2.
LCMS: m / z 390 [M + H] + HPLC retention time: 0.81 min (analysis condition A) [Example 26] Compound a6 5-bromo-2-ethylsulfanyl-benzaldehyde Sodium ethanethiolate (362 mg, 4.3 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (546 mg, 2.7 mmol) in DMF (1.08 ml) and the mixture was stirred at 60 ° C. After one hour, sodium ethanethiolate (123 mg, 1.5 mmol) was also added. The reaction solution was cooled to room temperature after 15 minutes and 1N hydrochloric acid aqueous solution was added, followed by extraction with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (163 mg, 24%) as a yellow oily substance.
H PLC retention time: 0.91 min (analysis condition A) 1 H-NMR (400 MHz, CDCl 3) d: 10.33 (1 H, s), 7.95 (1 H, d, J = 2. 2 Hz), 7.62 (1 H, dd, J = 2.2, 8.4 Hz), 7.30 (1 H, d, J = 8.4 Hz), 2. 97 (2H, q, J = 7.5 Hz), 1 .36 (3H, t, J = 7.5 Hz).
[Example 27] Compound a7 5-Bromo-2-ethylsulfanyl-benzaldehyde O-methyl-oxime Hydroxylamine-methylether hydrochloride (61 mg, 0.73 mmol) was added to a solution of 5-bromo-2-ethylsulfanyl-benzaldehyde (Compound a6, 163 mg, 0.66 mmol) in pyridine (0.42 ml) and the mixture was stirred. mix at room temperature for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with an aqueous solution of 1 N hydrochloric acid and then with saturated saline and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to yield a crude product of the title compound.
LCMS: m / z 274 [M + H] + HPLC retention time: 1 .10 min (analysis condition A) ío [Example 28] Compound a8 5-bromo-2-ethylsulfanyl-benzylamine ' 1 To a THF solution of the crude product of O-methyl-oxime of 5-bromo-2-ethylsulfanyl-benzaldehyde (Compound a7, 182 mg, 0.66 mmol), a solution of 1 mol / l of the borane-THF complex was added. on TH F (1.66 mL, 1.7 mmol) and the mixture was stirred at 80 ° C for 2.5 hours. The reaction mixture was cooled to 0 ° C and crushed ice and an aqueous solution of 1 N hydrochloric acid (3 ml) were added, followed by stirring at 90 ° C for one hour. The reaction solution was cooled to room temperature and separated by the addition of water and ethyl acetate. The aqueous layer was made basic with an aqueous solution of 5N sodium hydroxide, followed by three extractions with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to obtain a crude product of the title compound.
H PLC retention time: 0.48 min (analysis condition D) 1 H-NMR (400 MHz, CDCl 3) d: 7.48 (1 H, d, J = 2.2 Hz), 7.33 (1 H, dd, J = 2.2, 8.4 Hz), 7.17 (1 H, d, J = 8.4 Hz), 3.89 (2H, s), 2.93 (2 H, q, J = 7.5 Hz), 1.32 (3H, t, J = 7.5 Hz).
[Example 29] Compound a9 and (5-bromo-2-ethylsulfanyl-benzyl) carbamic acid Boc20 (0.148 mL, 0.64 mmol) was added to a solution of the crude product of 5-bromo-2-ethylsulfanyl-benzylamine (Compound a8) in TH F (2 mL) and the mixture was stirred at room temperature for one hour. . Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by column chromatography of silica gel (ethyl acetate / hexane) to yield the title compound (168 mg, total yield of Compound a6 in three steps: 73%) as a yellow oily substance.
[Example 30] Compound a10 Acid tert-butyl ester (5-bromo-2-ethanesulfonyl-benzylcarbamic acid MCPBA (234 mg, 1.02 mmol) was added to a solution of (5-bromo-2-ethylsulfanyl-benzyl) -carbamic acid fer-t-butylester (Compound a9, 168 mg, 0.49 mmol) in dichloromethane (2.4 ml) while cooling to 0 ° C. The mixture was then warmed to room temperature and stirred for four hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (180 mg, yield: 98%) as a yellow oily substance. [Example 31] Compound a1 1 5-bromo-2-ethanesulfonyl benzylamine hydrochloride .
A solution of 4N hydrochloric acid in ethyl acetate (2.4 ml) was added to (5-bromo-2-ethanesulfonyl-benzyl) carbamic acid terebutyl ester (Compound 10, 180 mg, 0.48 mmol) and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to yield the title compound (130 mg, yield: 87%) as a colorless solid.
[Example 32] Compound A-21 / V- (5-bromo-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide) DI PEA (0.050 ml, 0.29 mmol) was added to a solution of 5-bromo-2-ethanesulfonyl-benzylamine hydrochloride (Compound 1 1, 30.0 mg, 0.095 mmol), 3- (trifluoromethyl) -benzoic acid (19.9 mg , 0.1 1 mmol) and HBTU (39.8 mg, 0.1 1 mmol) in DCM (1 mL) under cooling in an ice water bath. The mixture was warmed Room temperature and stirred for 4.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Then the organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (42.5 mg, 99%) as a colorless solid.
LCMS: m / z 450 [M + H] + HPLC retention time: 0.87 min (analysis condition A) [Example 33] Compound A-22 / N / - (5-bromo-2-ethanesulfonyl-benzyl-3-chloro-5-trifluoromethyl-benzamide Synthesis of the title compound was carried out from 5-bromo-2-ethanesulfonyl-benzylamine hydrochloride (Compound a1 1) under the same conditions as for Compound A-21. However, 3-chloro-5- (trifluoromethyl) -benzoic acid was used in place of 3- (trifluoromethyl) -benzoic acid.
LCMS: m / z 484 [M + H] + HPLC retention time: 0.96 min (analysis condition A) [Example 34] Compound A-23 / V- (5-bromo-2-ethanesulfonyl-benzyl) -3-chloro-5-trifluoromethoxy-benzamide The title compound was synthesized from 5-bromo-2-ethanesulfonyl-benzylamine hydrochloride (Compound a 1 1) under the same conditions as for Compound A-21. However, 3-chloro-5- (trifluoromethoxy) -benzoic acid was used in place of 3- (trifluoromethyl) -benzoic acid.
LCMS: m / z 500 [M + H] + H PLC retention time: 0.98 min (analysis condition A) [Example 35] Compound A-24 A / - (5-bromo-2-ethanesulfonyl-benzyl-3-trifluoromethoxy-benzamide) The title compound was synthesized from 5-bromo-2-ethanesulfonyl-benzylamine hydrochloride (Compound a 1 1) under the same conditions as for Compound A-21. However, 3- (trifluoromethoxy) -benzoic acid was used in place of 3- (trifluoromethyl) -benzoic acid.
LCMS: m / z 466 [M + H] + HPLC retention time: 0.89 min (analysis condition A) [Example 36] C t A 25 The title compound was synthesized from 2,5-difluorobenzonitrile under the same conditions as for Compounds a1, a2 and A-1. However, the reaction was carried out at 90 ° C using sodium methanethiolate in place of ethanethiol and potassium carbonate under the conditions as for Compound a1; and 3-trifluoromethylbenzoic acid was used in place of 3-bromo-5- (trifluoromethyl) -benzoic acid under the conditions as for Compound A-1.
LCMS: m / z 344 [M + H] + HPLC retention time: 0.89 min (analysis condition A) [Example 37] Compound A-26 / \ M5-Fluoro-2-methanesulfonyl-benzyl) -3-trifluoromethyl-benzamide The title compound was synthesized from / V- (5-fluoro-2-methylsulfanyl-benzyl) -3-trifluoromethyl-benzamide (Compound A-25) under the same conditions as for Compound A-2.
LCMS: m / z 376 [M + H] HPLC retention time: 0.78 min (analysis condition A) [Example 38] Compound b1 Ethyl ester of 4-bromo-3-trifluoromethylbenzoic acid Potassium carbonate (1.5 g, 11.1 mmol) and ethyl iodide (1.2 g, 7.4 mmol) were added to a solution of 4-bromo-3-trifluoromethylbenzoic acid (1.0 g, 3.7 mmol). ) in DMF (5 ml) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, purify the resulting residue by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (1.03 g, 94%) as a brown oily substance. 1 H NMR (300 MHz, CDCl 3) d: 8.34 (1 H, d, J = 1 .9 Hz), 8.05 (1 H, dd, J = 8.4, 1 .9 Hz), 7.82 (1 H, d , J = 8.4 Hz), 4.44 (2H, q, J = 7.3 Hz), 1 .43 (3H, t, J = 7.3 Hz).
[Example 39] Compound b2 4- (4-Ethoxycarbonyl-2-trifluoromethyl-benzyl) -pi pe-1-carboxylic acid tert-butyl ester 4-Bromo-3-trifluoromethylbenzoic acid ethyl ester (Compound b, 1.03 g, 3.5 mmol), potassium 4-trifluoroboratomethylpiperazine-1-carboxylic acid fer-t-butyl ester (1.06 g, 3.5 mmol) was stirred. ), palladium acetate (40 mg, 0.17 mmol), X-fos (170 mg, 0.35 mmol) and cesium carbonate (3.39 g, 10.4 mmol) in a mixed THF / water solvent (10/1) (35 ml) ) at 90 ° C overnight. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by column chromatography on silica gel (ethyl acetate / hexane) to give the title compound (753 mg, 51%) as a colorless oily substance.
LCMS: m / z 417 [M + H] + HPLC retention time: 2.10 min (condition of analysis C) [Example 40] Compound b3 4- (4-carboxy-2-trifluoromethyl-benzyl) butyl ester - p i pe reason a n-1 -carboxylic Potassium hydroxide (203 mg, 3.6 mmol) was added to a mixed solution of 4- (4-ethoxycarbonyl-2-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound b2, 753 mg, 1. 8 mmol) in EtOH (14.4 ml) and water (3.6 ml) and the mixture was stirred at 30-45 ° C for six hours. The reaction mixture was neutralized to pH 5-6 by the addition of an aqueous solution of 1 N hydrochloric acid and then diluted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (MeOH / DCM) to produce the title compound (652 mg, 93%) as a colorless foamy substance.
LCMS: m / z 389 [M + H] + H PLC retention time: 1, 60 min (condition of analysis C) [Example 41] Compound b4 4- [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamom-2-trifluoromethyl-benzyl-piperazine-1-carboxylic acid terebutyl ester.
The title compound was synthesized from 4- (4-carboxy-2-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound b3) under the same conditions as for Compound A-14.
[Example 42] Compound B-1 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-3-trifluoromethyl-benzamide g g (4 ml) to a solution of tert-butyl ester of 4- [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl] -piperazine-1-carboxylic acid (Compound b4, 650 mg, 1.1 mmol) in DCM (12 mL) and stirred the mixture at room temperature for three hours. The reaction mixture was concentrated under reduced pressure and then diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the solvent was then concentrated under reduced pressure. The resulting residue was purified by chromatography on an amine silica gel column (MeOH / DCM) to yield the title compound (515 mg, 95%) as a colorless solid.
LCMS: m / z 504 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 43] Compound B-2 i \ / - (5-Chloro-2-ethanesulfonyl-benzyl) -4- (4-methyl-PID-Derazin-1-methylmethyl-3-trifluoromethyl-benzamide A suspension of / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-3-trifluoromethyl-benzamide (Compound B-1, 65 mg, 0.13 mmol) and paraformaldehyde (16 mg, 0.52 mmol) in formic acid (1 mL) was stirred at 80 ° C for one hour. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water and saturated saline, respectively, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH / DCM) and then by preparative TLC to yield the title compound (40 mg, 60%) as a colorless foamy substance.
LCMS: m / z 518 [M + H] + HPLC retention time: 0.53 min (analysis condition A) 15 [Example 44] Compound B-3 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4- (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoromethyl-benzamide Acetone (0.15 ml, 2.6 mmol) was added to a suspension of / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-3-trifluoromethyl-benzamide (Compound B-1, 65 mg, 0.13 mmol) and sodium triacetoxyborohydride (82 mg, 0.39 mmol) in THF (3.3 ml) and the mixture was stirred at 50-60 ° C for three hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water and saturated saline, respectively, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH / DCM) and then by silica gel column chromatography of amine (ethyl acetate / hexane) to yield the title compound (46 mg, 66%). as a colorless foaming substance.
LCMS: m / z 546 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 45] Compound B-4 A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-r4- (tetrahydro-pyran-4-yl) -piperazin-1-ylmethyl-3-trifluoromethyl-benzamide Tetrahydro-pyran-4-one (50 ml, 0.52 mmol) was added to a suspension of / N / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-3-trifluoromethyl-benzamide ( Compound B-1, 65 mg, 0.13 mmol) and sodium triacetoxyborohydride (82 mg, 0.39 mmol) in TH F (3.3 ml) and the mixture was stirred at 50-60 ° C for three hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water and saturated saline, respectively, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH / DCM) and then by preparative TLC to yield the title compound (47 mg, 62%) as a colorless foamy substance.
LCMS: m / z 588 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 46] Compound B-5 4-f4- (2-amino-acetyl) -piperazin-1-methylmethyl- / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide HATU (63 mg, 0.16 mmol) and DIPEA (29 mL, 0.16 mmol) were added to a solution of A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-3-trifluoromethyl- benzamide (Compound B-1, 83 mg, 0.16 mmol) and urea-butoxycarbonylamino-acetic acid (32 mg, 0.18 mmol) in DMF (1.6 mL) and the mixture was stirred at room temperature environment for three hours. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (2- {4- [4- (5-chloro)) fer-butyl ether. -2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl] -piperazin-1-yl} -2-oxo-ethylcarbamic acid (99 mg, 91%) as a colorless foamy substance.
TFA (0.5 ml) was added to a solution of (2- {4- [4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl] -piperazine-1-fer-butylester. il.) -2-oxo-ethylcarbamic acid (97 mg, 0.17 mmol) in DCM (1 mL) and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and then diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and then the solvent was concentrated under reduced pressure. The resulting residue was purified by chromatography on an amine silica gel column (MeOH / DCM) to yield the title compound (54 mg, 66%) as a colorless foamy substance.
LCMS: m / z 561 [M + H] + HPLC retention time: 0.47 min (analysis condition A) [Example 47] Compound b5 Etile t d -methyl-3-trifluoromethylbenzoic acid The title compound was synthesized from 4-methyl-3-trifluoromethylbenzoic acid under the same conditions as for Compound b1.
[Example 48] Compound b6 Ethyl ester of 4-bromomethyl-3-trifluoromethylbenzoic acid A solution of 4-methyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b5, 1.1 g, 4.8 mmol), NBS (936 mg, 5.3 mmol) and 70% benzoyl peroxide (165 mg, 0.48 mmol) was stirred. ) in carbon tetrachloride (24 ml) at 85 ° C for four hours. The reaction mixture was filtered with celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / hexane) to give the title compound (900 mg, 60%) as a colorless solid. 1 H-RM N (300 MHz, CDCl 3) d: 8.31 (1 H, d, J = 1.5 hours), 8.21 (1 H, dd, J = 8.0, 1.5 hz), 7.68 (1H, d, J = 8.0 Hz), 4.65 (2H, s), 4.42 (2 H, q, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz).
[Example 49] Compound b7 Ethyl ester 4 - ((R) -3-fe / c-butoxycarbonylamino-pyrrolidin-1- Ferric-butylester of (R) -pyrrolidin-3-yl-carbamic acid (404 mg, 2.2 mmol) and TEA (605 ml, 4.3 mmol) were added to a solution of 4-bromomethyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b6, 450 mg, 1.4 mmol) in DCM (7 mL) and the mixture was stirred at room temperature for three hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (590 mg, 98%) as a viscous oily substance.
H-NMR (300 MHz, CDCl 3) 6: 8.29 (1H, s), 8.18 (1H, d, J = 8. 2 Hz), 7.86 (1 H, d, J = 8.2 Hz), 4.83 (1 H, brs), 4.41 (2 H, q, J = 7. 2 Hz), 4.14-4.24 (1H, m), 3.82 (2H, s), 2.80-2.87 (1H, m), 2.65-2.70 (1 H, m), 2.54-2.58 (1H, m), 2.22-2.41 (2H, m), 1.57-1.61 (1H, m), 1.44 (9H, s), 1 .41 (3H, t, J = 7.2 Hz).
[Example 50] Compound b8 Acid 4 ((R) -3-fe / c-butoxycarbo ni lamin o- -3- trifluoromethylbenzoic acid An aqueous solution of 1 N sodium hydroxide was added (0.9 ml) to an ethyl ester solution of 4 - ((R) -3-fer-butoxycarbonylamino-pyrrolidin-1-ylmethyl) -3-trifluoromethyl benzoic acid (Compound b7, 192 mg, 0.46 mmol) in EtOH (2 ml) and the mixture was stirred at 40-65 ° C for one hour. The reaction mixture was neutralized by the addition of an aqueous solution of 1 N hydrochloric acid (0.9 ml) and then the solvent was concentrated under reduced pressure to obtain a crude product of the title compound.
[Example 51] Compound b9 ((R) -1-f4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl-pyrrolidin-3-yl) -carbamic acid tert-butylester The title compound was synthesized from 4 - ((R) - 3-ferc-butoxycarbonylamino-pyrrolidin-1-ylmethyl) -3-trifluoromethylbenzoic acid (Compound b8) under the same conditions as for Compound A-14.
[Example 52] Compound B-6 4 - ((R) -3-Amino-pyrrolidin-1-ylmethi-A / - (5-chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide The title compound was synthesized from acid fer-butyl ester. { (R) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl] -pyrrolidin-3-yl} -carbamic (Compound b9) under the same conditions as for Compound B-1.
LCMS: m / z 504 [M + H] HPLC retention time: 0.41 min (analysis condition A) [Example 53] Compound B-7 4 - ((R) -3-acetyl lamyl no-pyrrole id in-1 -i lmethyl) - / V- (5-chloro-2-ethanesulfon liben cyn-3-trifluoromethyl-benze mida Acetyl chloride (8.5 ml, 0.12 mmol) and TEA (27.7 ml, 0.20 mmol) were added to a solution of 4 - ((R) -3-amino-pyrrolidin-1-methylmethyl) - / V- (5 -chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B-6, 50 mg, 0.10 mmol) in DCM (1 mL) and the mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH / DCM) and then by preparative TLC (MeOH / DCM) to yield the title compound (39 mg, 72%) as a colorless foamy substance.
LCMS: m / z 546 [M + H] + H PLC retention time: 0.48 min (analysis condition A) [Example 54] Compound B-8 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-dimethylamino-pyrrolidin-1-methylmethyl) -3-trifluoromethyl-benzamide i The title compound was synthesized from 4 - ((R) -3- amino-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B-6) under the same conditions as for Compound B-2.
LCMS: m / z 532 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 55] Compound B-9 / V- (5-chloro-2-eta nsulfon i-benzyl-4 - ((R) -3-methansulfo ni lam i no-pyrro lidin-1-ylmethyl) -3-trifluoromethyl-benza mida .
Mesylate chloride (10 ml, 0.13 mmol) was added to a solution of 4 - ((R) -3-amino-pyrrolidin-1-methylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3 trifluoromethyl-benzamide (Compound B-6, 60 mg, 0.12 mmol) and TEA (17 mL, 0.12 mmol) in DCM (2 mL) under ice-cooling and the mixture was stirred at room temperature for eight hours. The reaction solution was diluted with DCM. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (methanol / DCM) to yield the title compound (49 mg, 82%). as a colorless solid.
LCMS: m / z 582 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 56] Compound B-10 Methyl ester ((R) -1-f4- (5-chloro-2-ethanesulfonyl-benzyl-rbamoyl) -2-trifluoromethyl-benzyl-pyrrolidin-3-yl) -carbamic acid Methyl chloroformate (10 ml, 0.12 mmol) and TEA (30 ml, 0.22 mmol) were added to a solution of 4 - ((R) -3-amino-pyrrolidin-1-methylmethyl) -A / - (5-chloro -2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B-6, 55 mg, 0.1 1 mmol) in DCM (1 mL) and the mixture was stirred at room temperature for two hours. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by preparative TLC (methanol / DCM) to yield the title compound (37 mg, 60%) as a pale yellow foamy substance.
LCMS: m / z 562 [M + H] + HPLC retention time: 0.52 min (analysis condition A) [Example 57] Compound B-1 1 / V- (5-chloro-2-eta nsulfo ni l-be nc¡n-3-trifluo romet i l-4 - ((R) -3-u re ido- pirro lid i n-1 -i ImetiD- benze mida gg co (0.8 ml) to a solution of 4 - ((R) -3-amino-pyrrolidin-1-ylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B-6, 80 mg, 0.16 mmol) in DCM (0.8 ml) and this was cooled to 0 ° C. Sodium cyanate was added to the mass (20.6 mg, 0.32 mmol) and the mixture was stirred at room temperature for two hours. The reaction solution was diluted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by preparative TLC (methanol / DCM) to yield the title compound (40.1 mg, 46%) as a pale colorless foamy substance.
LCMS: m / z 547 [M + H] + H PLC retention time: 0.48 min (condition of Analysis A) [Example 58] Compound B-12 4-G (R) -3- (2-amino-a-cedylamino) -pyr-rol id-n-1-ylmethyl] -A / - (5-Clo n-sulphonyl-benzyl-3-trifluoromethyl-benzamide) The title compound was synthesized from 4 - ((R) -3-amino-pyrrolidin-1-methylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -6) under the same conditions as for Compound B-5.
LCMS: m / z 561 [M + H] + H PLC retention time: 0.44 min (analysis condition A) [EXAM PLO 59] Compound b10 Ethyl ester of 4-r (R) -3- (ferc-butoxycarbonyl-methyl-amino) -pyrrolidin-1-ylmethyl-3-trifluoromethylbenzoic acid The title compound was synthesized from ethyl ester of 4-bromomethyl-3-trifluoromethylbenzoic acid (Compound b6) and methyl- (R) -pyrrolidin-3-yl-carbamic acid fer-butyl ester under the same conditions as for Compound b7.
[Example 60] Compound b1 1 Acid _ 4-G (R) -3- (tert-bu toxic rbon l-methyl-amino) -pyrrolidin-1-ylmethyl-3-trifluoromethylbenzoic acid The title compound was synthesized from 4 - [(R) -3- (urea-butoxycarbonyl-methyl-amino) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid ester (Compound b10) under the same conditions as for Compound b8, [Example 61] Compound b12 Acid tert-butylester. { (R) -1-f4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoy-2-trifluoromethyl-benzyl-pyrrolidin-3-ill-methyl-ba The title compound was synthesized from 4 - [(R) - 3- (ferc-bu toxica rbonyl-methylamino) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid (Compound b 1 1) using DCM instead of DMF under the same conditions as for Compound A- 14 [Example 62] Compound B-13 / V- (5-Chloro-2-ethanesulfonyl-benzyl-4 - ((R) -3-methylamino-pyrrolidin-1-ylmethyl) -3-trifluoromethyl-benzamide The title compound was synthesized from acid urea-butyl ester. { (R) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl] -pyrrolidin-3-yl} methyl-carbamic (Compound b12) under the same conditions as for Compound B-1.
LCMS: m / z 518 [M + H] + H PLC retention time: 0.49 min (analysis condition A) [Example 63] Compound b13 Ethyl ester of 4 - ((R) -3-Methylamino-pyrrolidin-1-methylmethin-3-trifluoromethylbenzoic acid The title compound was synthesized from 4 - [(R) -3- (ferc-butoxycarbonyl-methyl-amino) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid ethyl ester (Compound b 10) under the same conditions as for Compound B-1.
[Example 64] Compound b14 Ethyl ester of 4-f (R) -3- (methanesulfonyl-methyl-amino) -pyrrolidin-1-i I methyl-3-triflu promised I benzoic acid The title compound was synthesized from 4 - ((R) -3-methylamino-pyrrolidin-1-methylmethyl) -3-trifluoromethylbenzoic acid ethyl ester (Compound b1 3) under the same conditions as for Compound B-9.
[Example 65] Compound b15 4-r (R) -3- (methanesulfonyl-methyl-amino) -pyrrolidin-1-ylmethyl-H-3- trifluoromethyl benzoic acid The title compound was synthesized from 4 - [(R) -3- (methanesulfonyl-methyl-amino) -pyrrolidin-1-ylmethyl] -3- ethyl ester. trifluoromethylbenzoic acid (Compound b14) under the same conditions as for Compound b3.
[Example 66] Compound B-14 / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-r (R) -3- (methanesulfonyl-methyl-amino) -pyrrolidin-1-ylmetin-3-trifluoromethyl-benzamide p this title from 4 - [(R) -3- (methanesulfonyl-methyl-amino) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid (Compound b15) under the same conditions as for Compound A-14 .
LCMS: m / z 596 [M + H] + HPLC retention time: 0.56 min (analysis condition A) [Example 67] Compound B-15 4 - ((S) -3-amino-pyrrolidin-1-methylmethyl-A / - (5-chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide p sto title from ethilester of 4-bromomethyl-3-trifluoromethylbenzoic acid (Compound b6) and (S) -pyrrolidin-3-yl-carbamic acid-butyl ester under the same conditions as for Compounds b7, b8, b9 and B-6. However, potassium hydroxide was used instead of sodium hydroxide under the conditions as for Compound b8, LCMS: m / z 504 [M + H] + HPLC retention time: 0.41 min (condition of analysis A) [Example 68] Compound B-16 4 - ((S) -3-acetylamino-pyrrolidin-1-methylmethin-A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-amino-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -15) under the same conditions as for Compound B-7.
LCMS: m / z 546 [M + H] + HPLC retention time: 0.49 min (analysis condition A) [Example 69] Compound B-17 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4 - ((S) -3-dimethylamino-pyrrolidin-1-ylmethyl-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-amino-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -15) under the same conditions as for Compound B-2.
LCMS: m / z 532 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 70] Compound B-18 / V- (5-chloro-2-ethanesulfon i-benzyl) -4 - ((S) -3-methanesulfonyl-i-pyrro-lidin-1-ylmethyl) -3-trifluoromethyl-benzemide The title compound was synthesized from 4 - ((S) -3-amino-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -15) under the same conditions as for Compound B-9.
LCMS: m / z 582 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 71] Compound B-19 4 - ((R) -3-Amino-p -peridin-1-ylmethyl) -am5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide The title compound was synthesized from 4-bromomethyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b6) and (R) -piperidin-3-ylcarbamic acid-butylester under the same conditions as for the Compounds b7, b8, b9 and B-6. However, potassium hydroxide was used instead of sodium hydroxide under the conditions as for Compound b8, LCMS: m / z 518 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 72] Compound B-20 / V- (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-dimethylamino-p-peridin-1-methylmethin-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-piperidin-1-ylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -19) under the same conditions as for Compound B-2.
LCMS: m / z 546 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 73] Compound B-21 4 - ((R) -3-acetylamino-piperidin-1-methylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-piperidin-1-methylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -19) under the same conditions as for Compound B-7.
LCMS: m / z 560 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 74] Compound B-22 / V- (5-chloro-2-ethanesulfonyl-benzyl-4 - ((R) -3-methanesulfonylamino-rometi l-be nza mida The title compound was synthesized from 4 - ((R) -3-ami-no-piperidin-1-methylmethyl) - / S / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide ( Compound B-19) under the same conditions as for Compound B-9.
LCMS: m / z 596 [M + H] H PLC retention time: 0.54 min (analysis condition A) [Example 75] Compound B-23 A / - (5-Chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-4 - ((R) -3-ureido-piperidin-1-ylmethyl) -benzamide The title compound was synthesized from 4 - ((R) -3-amin o-piperidin-1-ylmethyl) - A / - (5-chloro-2-e-tansulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B-19) under the same conditions as for Compound B-1 1.
LCMS: m / z 561 [M + H] + H PLC retention time: 0.50 min (analysis condition A) [Example 76] Compound B-24 / V- (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-methylamino-piperidin-1-ylmethio-3-trifluoromethyl-benzamide The title compound was synthesized from 4-bromomethyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b6) and methyl- (R) -piperidin-3-ylcarbamic acid fer-butyl ester under the same conditions as for the Compounds b7, b8, b9 and B-6. However, the reaction was performed using DCM instead of DMF under the conditions as for Compound b9.
LCMS: m / z 532 [M + H] + HPLC retention time: 0.52 min (condition of analysis A) [Example 77] Compound b16 Ethyl ester 4 - ((S) -3-fe / c-butoxycarbonylamino-piperi d i n - 1 - i I methyl) -3-trifluoromethyl benzoic acid The title compound was synthesized from 4-bromomethyl-3-trifluoromethylbenzoic acid c-butylester (Compound b6) and (S) -piperidin-3-yl-carbamic acid under the same conditions as for Compound b7.
[Example 78] Compound B-25 4 - ((S) -3-amino- p -peridin-1-methylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide) The title compound was synthesized from 4 - ((S) -3-ferc-butoxycarbonylamino-piperidin-1-ylmethyl) -3-trifluoromethylbenzoic acid ethyl ester (Compound b16) under the same conditions as for Compounds b8, b9 and B-6. However, the reaction was performed using DCM instead of DMF under the conditions as for Compound b9.
LCMS: m / z 518 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 79] Compound B-26 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4 - ((S) -3-dinethylamino-piperidin-1-methylmethyl) -3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-methylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -25) under the same conditions as for Compound B-2.
LCMS: m / z 546 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 80] Compound B-27 4 - ((S) -3-acetylamino-p-peridin-1-methylmethyl- / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide ii O The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -25) under the same conditions as for Compound B-7.
LCMS: m / z 560 [M + H] + HPLC retention time: 0.51 min (condition of Analysis A) [Example 81] Compound B-28 A / - (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((S) -3-methanesulfonylamino-p-peridin-1-methylmethin-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -25) under the same conditions as for Compound B-9.
LCMS: m / z 596 [M + H] + H PLC retention time: 0.54 min (analysis condition A) [Example 82] Compound B-29 / V- (5-Chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-4 - ((Sl-3-ureido-piperidin-1-ylmethyl-benzamide The title compound was synthesized from 4 - ((S) -3- amino-piperidn-1 -i I m eti I) -L / - (5-c lo ro-2 -eta nsu Ifon i Ibe nc I) -3-trifluoromethyl-benzamide (Compound B-25) under the same conditions as for Compound B-1 1.
LC S: m / z 561 [M + H] + HPLC retention time: 0.49 min (analysis condition A) [Examples 83 to 88] The compounds of the following Table 3 were synthesized using 4 - ((S) -3-amino-piperidin-1-ylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B-25) and the corresponding amino acids under the same conditions as for Compound B-5.
[Table 3] [Example 89] Compound B-33 4-((S) -3- (2-amino-2-methyl-propionylamino) -piperidin-1-methylmethyl-A / - (5- chloro-2-ethanesulfonyl-benzin-3-triflii promised l-benzamide A solution of 2- (9H-fluoren-9-ylmethoxycarbonylamino) -2-methyl-propionic acid (38 mg, 0.12 mmol) and HATU (52 mg, 0.14 mmol) in DMF (1 mL) was stirred for five minutes. Then 4 - ((S) -3-amino-piperidin-1-methylmethyl) - / V- (5-cl or ro-2-eta nsu mess nor l-benzyl) -3-trifluoromethyl-1-benzamide was added ( Compound B-25, 65 mg, 0.1 1 mmol) and DI PEA (55 mL, 0.32 mmol) and the mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and then the solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel of amine (ethyl acetate / hexane) to yield 9H-fluoren-9-ylmethyl ester of (1 -. {(S) -1 - [4- (5 2-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl] -piperidin-3-ylcarbamoyl} -1-methyl-ethyl) -carbamic acid (60 mg, 70%) as a colorless solid.
LCMS: m / z 825 [M + H] + HPLC retention time: 3.17 min (condition of analysis C) Piperidine (0.14 ml, 0.14 mmol) was added to a solution of 9/7-fluoren-9-ylmetilester of (1 - { (S) -1 - [4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) ) -2-trifluoromethyl-benzyl] -piperidin-3-ylcarbamoyl} -1-methyl-ethyl) -carbamic acid (60 mg, 0.073 mmol) in DCM 5 (0.73 ml) and the mixture was stirred at room temperature for two hours. hours. The reaction mixture was diluted with DCM and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and then the solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel of amine (ethyl acetate / hexane) to yield the title compound (25 mg. 57%) as a colorless solid.
LCMS: m / z 603 [M + H] 15 H PLC retention time: 0.44 min (analysis condition A) [Example 90 Compound b17 4-f (S) -3- (ferc-butoxycarbonyl-methyl-amino) -piperidine-1-i-methyl-3-trifluoromethylbenzoic acid A dispersion of 60% sodium hydride in mineral oil 25 (dispersion in oil) (195 mg, 4.9 mmol) was added to a Ethyl ester solution 4 - ((S) -3-ert-butoxycarbonylamino-piperidin-1-methylmethyl) -3-trifluoromethylbenzoic acid (Compound b16, 625 mg, 1.5 mmol) in THF (5.2 ml) under ice-cooling and methyl iodide (0.3 ml, 4.9 mmol) was further added. The reaction solution was stirred at room temperature overnight and water was added thereto. After extraction with ethyl acetate, the extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and concentration was performed under reduced pressure to yield the title compound as a crude product.
[Example 91] Compound b18 Ethyl ester of 4-f (S) -3- (ferc-butoxycarbonyl-meth1-amino-1-piperidin-1-i-Imet-ll-3-trifluoro-methyl-benzoic acid The title compound was synthesized from the crude product of 4 - [(S) -3- (ferc-butoxycarbonyl-methyl-amino) -piperidin-1-ylmethyl] -3-trifluoromethylbenzoic acid (Compound b 17) under the same conditions as for Compound b1.
[Example 92] Compound B-37 / V- (5-Chloro-2-ethanesulfonyl-benzyl-4 - ((S) -3-methylamino-piperidin-1 - MmetiD-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - [(S) -3- (urea-butoxycarbonyl-methyl-amino) -piperidin-1-ylmethyl] -3-trifluoromethyl-benzoic acid ethyl ester (Compound b18) under the same conditions as for Compounds b8, b9 and B-6. However, the reaction was performed using DCM instead of DMF under the conditions as for Compound b9.
LCMS: m / z 532 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 93] Compound b19 Ethyl ester of 4-f (S) -3- (fe / c-butoxycarbonylamino-methyl) -pyrrolidin-1-methylmethin-3-trifluoromethylbenzoic acid The title compound was synthesized from 4-bromomethyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b6) and (R) -1-pyrrolidin-3-ylmethylcarbamic acid fer-butyl ester under the same conditions as for Compound b7.
[Example 94] Compound B-38 4 - ((S) -3-aminomethyl-pyrrolidin-1-ylmethyl) - / \ M5 -chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - [(S) -3- (urea-butoxycarbonylamino-methyl) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid ethyl ester (Compound b19) under the same conditions as for Compounds b3, b4 and B-1. However, the reaction was performed using DCM instead of DMF under the conditions as for Compound b4.
LCMS: m / z 518 [M + H] + H PLC retention time: 0.39 min (analysis condition A) [Example 95] Compound B-39 / \ M5-Chloro-2-ethanesulfonyl-benzyl-4 - ((S) -3-dimethylaminomethyl-pyrrolidin-1-ylmethyl-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3- aminomethyl-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B-38) under the same conditions as for Compound B-2.
LCMS: m / z 546 [M + H] + HPLC retention time: 0.41 min (analysis condition A) [Example 96] Compound B-40 4-r (S) -3- (Acetylamino-methy-pyrrolidin-1-ylmetin-A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide title t from 4 - ((S) -3-aminomethyl-pyrrolidin-1-methylmethyl) - / / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B- 38) under the same conditions as for Compound B-7.
LCMS: m / z 560 [M + H] + H PLC retention time: 0.49 min (analysis condition A) [Example 97] Compound B-41 / V- (5-Chloro-2-ethanesulfonyl-benzin-4-r (R) -3- (methanesulphonylamino-methyl-D-pyrrolidin-1-Mmethi-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-aminomethyl-pyrrolidin-1-ylmethyl) - / / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl- benzamide (Compound B-38) under the same conditions as for Compound B-9.
LCMS: m / z 596 [M + H] + H PLC retention time: 0.51 min (analysis condition A) [Example 98] Compound b20 4 - [(S) -3- (urea-butoxycarbonylamino-methyl) -pyrrolidin-1-ylmethyl] -3-trifluoromethyl benzoic acid The title compound was synthesized from 4 - [(S) -3- (fe / c-butoxycarbonylamino-methyl) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid ethyl ester (Compound b19) under the same conditions as for Compound b8, however, the reaction was carried out at room temperature.
LCMS: m / z 403 [M + H] + HPLC retention time: 1.35 min (condition of E analysis) [Example 99] Compound b21 4 - ((R) -3-r (fe / c-butoxycarbonyl-methyl-amino) -methyl-1-pyrrolidin-1-ylmethyl) -3-trifluoromethylbenzoic acid A dispersion of 60% sodium hydride in mineral oil (oil dispersion) (36.5 mg, 0.91 mmol) was added to a solution of 4 - [(S) -3- (urea-butoxycarbonylamino-methyl) -pyrrolidin-1 - ylmethyl] -3-trifluoromethylbenzoic acid (Compound b20, 92 mg, 0.23 mmol) in THF under ice-cooling and the mixture was stirred at room temperature for 0.5 hour. Methyl iodide was added thereto (57.8 ml, 0.93 mmol) and the mixture was stirred at room temperature for two hours. Water was added to the reaction solution. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentration was performed under reduced pressure to produce the title compound as a crude product.
[Example 100] Compound b22 Tere- butylester of f (R) -1-r4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl-pyrrolidin-3-ylmethyl) -methyl- carbamic The title compound was synthesized from 4-acid. { (R) -3 - [(ferc-butoxycarbonyl-methyl-amino) -methyl] -pyrrolidin-1-ylmethyl} -3- trifluoromethylbenzoic acid (Compound b21) using DCM instead of DMF under the same conditions as for Compound A-14. [Example 101] Compound B-42 / \ M5-Chloro-2-ethanesulfonyl-benzyl-4 - ((S) -3-methylaminomethyl-pyrrolidin-1-ylmethyl-D-3-trifluoromethyl-benzamide The title compound was synthesized from acid fer-butyl ester. { (R) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2- t rif I uorometi l-be nci l] -p irol id i h-3-il metí l} -methylcarbamate (Compound b22) under the same conditions as for Compound B-1.
LCMS: m / z 532 [M + H] + H PLC retention time: 0.40 min (analysis condition A) [Example 102] Compound b23 Ethyl ester of 4-r (R) -3- (ferc-butoxycarbonylamino-metho-pyrrolidin-1-ylmethin-3-trifluoromethylbenzoic acid The title compound was synthesized from 4-bromomethyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b6) and c-butyl ester of (S) -1-pyrrolidin-3-ylmethylcarbamic acid under the same conditions as for the Compound b7.
[Example 103] Compound B-43 4 - ((R) -3-aminomethyl-pyrrolidin-1 -ylmethi-A / - (5-chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - [(R) -3- (fe / c-butoxycarbonylamino-methyl) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid ester (Compound b23) under the same conditions as for Compounds b3, b4 and B-1. However, the reaction was performed using DCM instead of DMF under the conditions as for Compound b4.
LCMS: m / z 518 [M + H] + H PLC retention time: 0.40 min (analysis condition A) [Example 104] Compound B-44 / V- (5-Chloro-2-ethanesulfonyl-benzyl-4 - ((R) -3-dimethylaminomethyl-pyrrolidin-1-methylmethyl) -3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-aminomethyl-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -43) under the same conditions as for Compound B-2.
LCMS: m / z 546 [M + H] HPLC retention time: 0.41 min (analysis condition A) [Example 105] Compound B-45 4-r (R) -3- (acetylamino-metiP-pyrrolidin-1-methylmethyl- / V- (5-chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-aminomethyl-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzM) -3-trifluoromethyl-benzamide (Compound B -43) under the same conditions as for Compound B-7.
LCMS: m / z 560 [M + H] + HPLC retention time: 0.48 min (analysis condition A) [Example 106] Compound B-46 / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-r (S) -3- (methanesulfonylaminomethyl) -pyrrolidin-1-methylmethin-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-aminomethyl-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -43) under the same conditions as for Compound B-9.
LCMS: m / z 596 [M + H] + H PLC retention time: 0.51 min (analysis condition A) [Example 107] Compound b24 Etilester of 4 - ((S) -3-f (ferc-butoxycarbonyl-methyl-amino) acid - Metin-pyrrolidin-1-methylmethyl} -3-trifluoromethylbenzoic acid The title compound was obtained as a crude product from 4 - [(R) -3- (ferric-bu toxica rbonilamin o-methyl) -pyridin-1-ylmethyl] -3-trifluoromethylbenzoic acid ethyl ester ( Compound b23) under the same conditions as for Compound b21.
[Example 108] Compound b25 4- Acid. { (S) -3-riferc-butoxycarbonyl-methyl-amino) -methyl-pyrrolidin-1-ylmethyl) -3-trifluoromethylbenzoic acid The title compound was obtained from the crude product of 4-ethyl ester. { (S) -3 - [(fe / c-Butoxycarbonyl-methyl-amino) -methyl] -pyridin-1-ylme ti l} -3-trifluoromethylbenzoic acid (Compound b24) under the same conditions as for Compound b3. [Example 109] Compound b26 Tere-butyl ester of acid. { 1 -r4- (5-chloro-2-ethanesulfonyl- benzylcarbamom-2-trifluoromethyl-benzyl-pyrrolidin-3-ylmethyl > -methyl-carbamic II The title compound was synthesized from 4-acid. { (S) -3 - [(ert-butoxycarbonyl-methyl-amino) -methyl] -pyrrolidin-1-ylmethyl} -3- trifluoromethylbenzoic acid (Compound b25) under the same conditions as for Compound A-14.
[Example 1 10] Compound B-47 A / - (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-methylaminomethyl-pyrrolidin-1-methylmethin-3-trifluoromethyl-benzamide The title compound was synthesized from acid fer-butyl ester. { (S) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2- trifluoromethyl-benzyl] -pyrrolidin-3-ylmethyl} -methyl-carbamic (Compound b26) under the same conditions as for Compound B-1.
LCMS: m / z 532 [M + H] + HPLC retention time: 0.41 min (analysis condition A) [Example 1 1 1] Compound B-48 / V- (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-hydroxy-pyrrolidin-1-ylmethyl) -3-trifluoromethyl-benzamide The title compound was synthesized from 4-bromomethyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b6) and (R) -pyrrolidin-3-ol under the same conditions corresponding to compounds b7, b8 and b9. However, potassium hydroxide was used in place of sodium hydroxide under the conditions as for Compound b8.
LCMS: m / z 505 [M + H] + HPLC retention time: 0.49 min (analysis condition A) [Example 1 12] Compound B-49 / V- (5-chloro-2-ethanesulfonyl-benzin-4 - ((R) -3-methoxy-pyrrolidin-1-ylmetin-3-trifluoromethyl-benzamide p this title from ethyl ester of 4-bromomethyl-3-trifluoromethylbenzoic acid (Compound b6) and (R) -3-methoxy-pyrrolidine under the same conditions as for Compounds b7, b8 and b9. However, potassium hydroxide was used in place of sodium hydroxide under the conditions as 5 for Compound b8, LCMS: m / z 519 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 1 13] Compound B-50 / V- (5-Chloro-2-ethanesulfonyl-benzyl-4-pyrrolidin-1-ylmethyl-3-trifluoride methyl I-be nza mide The title compound was synthesized from 4-bromomethyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b6) and pyrrolidine under the same conditions as for Compounds b7, b8 and b9. However, potassium hydroxide was used in place of sodium hydroxide under the conditions as for Compound b8.
LCMS: m / z 489 [M + H] + HPLC retention time: 0.51 min (condition of 5 analysis A) [Example 1 14] Compound b27 2-amino-4-chloro-5-trifluoromethylbenzoic acid ester Boc20 (53.3 mL, 240 mmol) was added to a suspension of 2-bromo-5-chloro-4-trifluoromethyl-phenylamine (26.8 g, 98 mmol) and DMAP (2.39 g, 20 mmol) in THF (500 mL) and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield 4- (b- (tert-butoxycarbonyl) amino) -5- Bromo-2-chloro-1-trifluoromethylbenzene (45.9 g, 99%) as a colorless solid.
HPLC retention time: 1.12 min (analysis condition A) 1 H NMR (400 MHz, CDCl 3) d: 7.92 (1 H, s), 7.40 (1 H, s), 1.43 (18 H, s).
A 1.57 M solution of N-buLi in hexane (33 ml, 52 mmol) was added to a solution of 4- (bis (ferc-butoxycarbonyl) amino) -5-bromo-2-chloro-1-trifluoromethylbenzene (20.5 g, 43 mmol) in THF (430 mL) for 10 minutes at -78 °. C and then stirred for one hour. A saturated aqueous solution of ammonium chloride (200 ml) was added thereto and then the mixture was heated to a room temperature. Ethyl acetate (400 ml) was added thereto and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration.
After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield 2-fert-butoxycarbonylamino-4-chloro-5-trifluoromethylbenzoic acid terebutyl ester ( 13.9 g, 82%) as a colorless solid ío HPLC retention time: 1.29 min (analysis condition A) 1 H NMR (400 MHz, CDCl 3) d: 10.55 (1 H, s), 8.72 (1 H, s), 8.22 (1 H, s), 1.62 (9H, s), 1.55 (9H , s).
Trifluoroacetic acid (88 ml) was added to a solution of 2-ferc-butoxycarbonylamino-4-chloro-5-trifluoromethylbenzoic acid ferric-butyl ester (13.9 g, 35 mmol) in DCM (350 ml) and the mixture was stirred at room temperature. room temperature for 15 hours. The reaction solution was concentrated under reduced pressure to yield 2-amino-4-chloro-5-trifluoromethylbenzoic acid as a crude product.
LCMS: m / z 240 [M + H] + HPLC retention time: 0.71 min (condition of analysis A) Potassium carbonate (19.4 g, 141 mmol) and iodide were added Ethyl (4.22 ml, 53 mmol) was added to a solution of the crude product of 2-amino-4-chloro-5-trifluoromethylbenzoic acid, which was obtained as mentioned above, in DMF (176 ml) and the mixture was stirred at room temperature for two hours. Water (1 70 ml) was added to the reaction solution. After extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield 2-amino-4-chloro-5-trifluoromethylbenzoic acid ethyl ester (5.89 g, 63%) as a yellow solid.
LCMS: m / z 268 [M + H] + HPLC retention time: 0.93 min (analysis condition A) [Example 1 15] Compound b28 2-Amino-5-trifluoromethyl-4-vinyl-benzoic acid ethyl ester Distilled water (12 ml) was added to a suspension of 2-amino-4-chloro-5-trifluoromethylbenzoic acid ethyl ester (Compound b27, 9.00 g, 34 mmol), potassium vinyltrifluoroborate (6.31 g, 47 mmol) , BuPAd2 (1.21 g, 3.4 mmol), palladium acetate (378 mg, 1.7 mmol) and potassium carbonate (13.9 g, 100 mmol) in toluene (336 mL) and the mixture was stirred at 90 ° C under an argon atmosphere for 18 hours. The reaction solution was cooled to room temperature and then ethyl acetate was added thereto and washed with water. The organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (7.93 g, 91%) as a yellow solid.
LCMS: m / z 260 [M + H] + HPLC retention time: 0.94 min (analysis condition A) [Example 1 16] Compound b29 Ethyl ester _ 2-amino-4- (1,2-dihydroxy-ethyl) -5- t rif I or methyl benzoic gold A mixture of AD-mix-a (61.3 g) in t-buOH / water (140 ml / 140 ml) was stirred at room temperature for five minutes. A mixture of 2-amino-5-trifluoromethyl-4-vinylbenzoic acid ethyl ester (Compound b28, 14.4 g, 56 mmol) in t-buOH / water (140 ml / 140 ml) was added to this reaction solution and the mixture was stirred at room temperature for 0.5 hour. Sodium nitrite (35.1 g) was added to the reaction mixture and the mixture was stirred at room temperature for one hour. Ethyl acetate was added to the reaction mixture. After washing with saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the obtained solid was washed with DCM to yield the title compound (12.9 g, 79%) as a colorless solid.
LCMS: m / z 294 [M + H] + HPLC retention time: 0.63 min (analysis condition A) [Example 1 17] Compound b30 Ethyl ester of 2-amino-4-formyl-5-trifluoromethyl-benzoic acid Water (273 ml) and sodium periodate (16.4 g, 76 mmol) were added to a solution of 2-amino-4- (1,2-dihydroxy-ethyl) -5-trifluoromethylbenzoic acid ethyl ester (Compound b29, 16.0 g , 54 mmol) in TBME (546 ml) and the mixture was stirred at room temperature for seven hours. TBME was added to the mixture reaction. After washing with a saturated aqueous solution of sodium chloride, the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentration was performed under reduced pressure to yield the title compound (14.1 g, 99%) as a yellow solid.
LCMS: m / z 262 [+ H] + HPLC retention time: 0.87 min (analysis condition A) [Example 1 18] Compound b31 Ethyl ester of 4-formyl-3-trifluoromethylbenzoic acid Sodium nitrite (2.6 g, 38.3 mmol) was added to a solution of 2-amino-4-formyl-5-trifluoromethyl acid ethyl ester (Compound b30, 1.00 g, 3.83 mmol) in formic acid (12 ml). ) under cooling with ice and the mixture was stirred under ice cooling for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added thereto. After extraction with ethyl acetate, the extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the The resulting residue was chromatographed on a silica gel column (ethyl acetate / hexane) to yield the title compound (650 mg, 71%).
H-NMR (300 MHz, CDCl 3) d: 10.44 (1 H, s), 8.44 (1 H, s), 8. 34 (1 H, d, J = 8.2 Hz), 8.20 (1 H, d, J = 8.2 Hz), 4.46 (2 H, q, J = 7.1 Hz), 1.44 (3 H, t, J = 7.1 Hz ).
[Example 1 19] Compound b32 4-F (S) -2- (ferc-butoxycarbonylamino-methyl) -pyridine lidin-1-lmethin-3-trifluoromethylbenzoic acid ester Ferric (S) -1-pyrrolidin-2-ylmethylcarbamic acid (488 mg, 2.4 mmol) and sodium triacetoxyborohydride (516 mg, 2.4 mmol) were added to a solution of 4-formyl-3-ethyl ester. trifluoromethylbenzoic acid (Compound b31, 200 mg, 0.81 mmol) in THF (8 mL) and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by column chromatography on silica gel (ethyl acetate / hexane) to give the title compound (265 mg, 76%) as an oily substance. 1 H-NMR (300 MHz, CDCl 3) d: 8.29 (1H, s), 8.18 (1H, d, J = 8. 2 Hz), 7.85 (1 H, d, J = 8.2 Hz), 4.83 (1 H, brs), 4.41 (2 H, q, J = 7. 2 Hz), 4.11 (1 H, d, J = 14.8 Hz), 3.63 (1 H, d, J = 14.8 Hz), 3.37- 3.26 (1 H, m), 3.14-3.06 (1H, m), 2.95-2.89 (1H, m), 2.82-2.72 (1H, m), 2.23-2.14 (1H, m), 1.99-1.89 (1H, m), 1.78-1.62 (3H, m), 1.44 (9H, s), 1.41 (3H, t, J = 7.2 Hz).
[Example 120] Compound b33 4-f (S) -2- (ferc-butoxycarbonylamino-methyl) -pyrrolidin-1-i-methyl-H-3-triflu or romethyl-benzoic acid The title compound was synthesized from 4 - [(S) -2- (fe / c-butoxycarbonylamino-methyl) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid ethyl ester (Compound b32) under the same conditions as for Compound b8.
[Example 121] Compound b34 butyl ester of l (S) -1-f4- (5-chloro-2-ethanesulfonyl- benzylcarbamoyl) -2-trifluoromethyl-benzyl-1-pyrrolidm-2-ylmethyl) - carbamic The title compound was synthesized from 4 - [(S) -2- (fer-butoxycarbonylamino-methyl) -pyrrolidin-1-ylmethyl] -3-trifluoromethylbenzoic acid (Compound b33) under the same conditions as for Compound A -14.
[Example 122] Compound B-51 4 - ((S) -2-aminomethyl-pyrrolidin-1-i I methyl) - / V- (5-chloro-2-ethanesulfon ji be ncil) -3-trifl uoromet i l-benza mida The title compound was synthesized from acid fer-butyl ester. { (S) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl] -pyrrolidin-2-ylmethyl} -carbamic (Compound b34) under the same conditions as for Compound B-1.
LCMS: m / z 518 [+ H] + HPLC retention time: 0.50 min (analysis condition A) [Examples 123 to 125] The compounds of Table 4 below were synthesized using 4-formyl-3-trifluoromethylbenzoic acid ethyl ester (Compound b31) and the corresponding cyclic amines under the same conditions as for Compounds b32, b33, b34 and B-51.
[Table 4] [Example 126] Compound B-52 hH 5-chloro-2-ethanesulfonyl-benzyl-4-dimethylamine omethyl- pirro lidin-1 -ilmetih-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -2-aminomethyl-pyrrolidin-1-methylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -51) under the same conditions as for Compound B-2.
LC S: m / z 546 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 127] Compound B-55 Chloro-2-ethanesulfonyl-benzyl-4- (2-dimethylaminomethyl- pyrrolidin-1-ylmethyl-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -2-aminomethyl-pyrrolidin-1-methylmethyl) - / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B-54) under the same conditions like for Compound B-2 LCMS: m / z 546 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 128] Compound b35 4-dibromomethyl-3-trifluoromethylbenzoic acid NBS (2.18 g, 12 mmol) and BP0 / H20 (79.1 mg, 0.24 mmol) were added to a solution of 4-methyl-3-trifluoromethylbenzoic acid (1.00 g, 4.9 mmol) in CCI4 (20 mL) and the mixture was heated under reflux for 24 hours. Hexane was added to the reaction mixture and extraction with a 0.5 N aqueous sodium hydroxide solution. An aqueous solution of 0.5N hydrochloric acid was added and extraction was carried out with isopropyl acetate and cyclopentylmethylether. The organic layer was then washed with saturated saline solution and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentration was performed under reduced pressure to yield the title compound (1.78 g, 100%) as a pale yellow powder.
LCMS: m / z 359 [M-H] - Retention time of H PLC: 0.81 min (condition of Analysis A) [Example 129] Compound b36 4-formyl-3-trifluoromethylbenzoic acid An aqueous solution (7 ml) of silver nitrate (2.04 g, 12 mol) was added to a solution of 4-dibromomethyl-3-trifluoromethylbenzoic acid (Compound b35, 1.74 g, 4.8 mmol) in acetone (35 ml). and the mixture was stirred at 60 ° C for 26 hours. An aqueous solution (1 ml) of silver nitrate (407 mg, 2.4 mmol) was added to the mass and the mixture was stirred at 60 ° C for an additional 16 hours. Isopropyl acetate and an aqueous solution of 1 N hydrochloric acid were added to the reaction mixture and the solid was removed by filtration. The filtrate was extracted twice with isopropyl acetate and then the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentration was performed under reduced pressure to produce the title compound as a crude product.
[Example 130] Compound b37 / V / - (5-chloro-2-ethanesulfonyl-benzyl) -4-formyl-3-trifluoromethyl-benzamide The title compound was synthesized from the crude product of 4-formyl-3-trifluoromethylbenzoic acid (Compound b36) under the same conditions as for Compound A-14. [Example 131] Compound b38 F (S) -1-F4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoy-2-trifluoromethyl-benzyl-1-piperidin-3-ylmethyl} -carbamic acid tert-butyl ester The title compound was synthesized from / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-formyl-3-trifluoromethyl-benzamide (Compound b37) under the same conditions as for Compound b32. However, the reaction was carried out using chloroform instead of THF as the solvent and (R) -1-piperidin-3-ylmethylcarbamic acid fer-butylester instead of (S) -1-pyrrolidin- tert-butylester. 2-ylmethylcarbamic acid.
[Example 132] Compound B-57 4 - ((S) -3-aminomethyl-piperdin-1-methylmethin-A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide A 4N solution of hydrochloric acid in ethyl acetate (3 mL) was added to a solution of acid fer-t-butylester. { (S) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-benzyl] -piperidin-3-ylmethyl} -carbamic acid (Compound b38.267 mg, 0.42 mmol) in ethyl acetate (1 mL) and the mixture was stirred at room temperature for one hour. An aqueous solution of 1 N sodium hydroxide was added to the reaction mixture and extraction was carried out with ethyl acetate. The organic layer was then washed with saturated saline solution and dried over anhydrous sodium sulfate. The drying agent was removed by filtration. After concentration under reduced pressure, the resulting residue was purified by chromatography on an amine silica gel column (methanol / ethyl acetate) to yield the title compound (186 mg, 83%) as a colorless foamy substance.
LCMS: m / z 532 [M + H] + HPLC retention time: 0.42 min (analysis condition A) [Example 133] Compound B-58 A / - (5-Chloro-2-ethanesulfonyl-benzyl) -4 - ((S) -3-dimethylaminomethyl-p-peridin-1-methylmethyl) -3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-aminomethyl-piperidin-1-methylmethyl) - / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide ( Compound B-57) under the same conditions as for Compound B-2.
LCMS: m / z 560 [M + H] + HPLC retention time: 0.43 min (analysis condition A) 15 [Example 134] Compound B-59 4-f (S) -3- (Acetylamino-methyl) -piperidin-1-methylmeth- / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-aminomethyl-piperidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3- 25 trifluoromethyl-benzamide (Compound B-57) using DMF instead of DCM under the same conditions as for Compound B-7.
LCMS: m / z 574 [M + H] + H PLC retention time: 0.51 min (analysis condition A) [Example 135] Compound B-60 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4-r (R) -3- (methanesulfonylamino-methyl P-p i pe rid in-1 - i I metíll-3-triflu prometí l-be nzam ida The title compound was synthesized from 4 - ((S) -3-aminomethyl-piperidin-1-methylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -57) using DMF instead of DCM under the same conditions as for Compound B-9.
LCMS: m / z 610 [M + H] + H PLC retention time: 0.53 min (analysis condition A) [Example 136] Compound B-61 4-f (S) -3-f (2-amino-acetylamino) -methyl-piperidin-1-ylmethyl) -A / - (5- chloro-2-ethoxyl n-sulphonyl) -3-trifluoromethyl- benze mida The title compound was synthesized from 4 - ((S) -3-aminomethyl-piperidin-1-methylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -57) using hydrochloric acid / ethyl acetate in place of TFA / DCM under the same conditions as for Compound B-5.
LCMS: m / z 589 [M + H] + H PLC retention time: 0.44 min (analysis condition A) [Examples 137 to 139] The compounds of Table 5 below were synthesized using A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-formyl-3-trifluoromethyl-benzamide (Compound b37) and the corresponding cyclic amines under the same conditions as for the Compounds b38 and B-57.
[Table 5] [Example 140] Compound B-64 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-dimethylaminomethyl-piperidin-1-ylmethyl-3-trifluoromethyl-benzamide I The title compound was synthesized from 4 - ((R) -3-aminomethyl-piperidin-1-methylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -63) under the same conditions as for Compound B-2.
LCMS: m / z 560 [M + H] + HPLC retention time: 0.44 min (analysis condition A) [Example 141] Compound B-65 4-f (R) -3- (acetylamino-metin-p-peridin-1-ylmethyl- / V- (5-chloro-2-ethanesulfonyl-benzyl-3-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-aminomethyl-piperidin-1-methylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -63) using DMF instead of DCM under the same conditions as for Compound B-7.
LCMS: m / z 574 [M + H] + HPLC retention time: 0.52 min (analysis condition A) [Example 142] Compound B-66 / \ / - (5-Chloro-2-ethanesulfonyl-benzyl-4-r (S) -3- (methanesulfonyl-trifluoromethyl-benzamide) The title compound was synthesized from 4 - ((R) -3-aminomethyl-piperidin-1-methylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethyl-benzamide (Compound B -63) using DMF instead of DCM under the same conditions as for Compound B-9.
LCMS: m / z 610 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 143] Compound d 4-Chloro-3-trifluoromethoxy-benzoic acid ester The title compound was prepared from 4-chloro-3-trifluoromethoxy-benzoic acid under the same conditions as for Compound b1.
[Example 144] Compound c2 4- (4-Ethoxycarbonyl-2-trifluoromethoxy-benzyl-piperazine-1-carboxylic acid tert -butylester Title item from ethyl ester of 4-chloro-3-trifluoromethoxy-benzoic acid (Compound c1) under the same conditions as for Compound b2.
[Example 145] Compound c3 Tere-butyl ester of 4- (4-carboxy-2-trifluoromethoxy-benzyl-piperazine-1-carboxylic acid) The title compound was synthesized from 4- (4-ethoxycarbonyl-2-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound c2) under the same conditions as for Compound b3.
[Example 146] Compound c4 butyl ester _ of _ acid _ 4-f4- (5-chloro-2-ethanesulfonyl- Benzylcarbamoyl-2-trifluoromethoxy-benzyl-piperazine-1-carboxylic acid The title compound was synthesized from 4- (4-carboxy-2-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid (C3) -butyl ester under the same conditions as for Compound A-14.
[Example 147] Compound C-1 / V- (5-chloro-2-ethanesulfonyl- -1-methylmethyl-3-trifluoromethoxy-benzamide The title compound was synthesized from 4- [4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethoxy-benzyl] -piperazine-1-carboxylic acid (Compound c4) under the same conditions as for the Compound B-1.
LCMS: m / z 520 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 148] Compound C-2 A / - (5-Chloro-2-ethanesulfonyl-benzin-4- (4-methyl-piperazin-1-ylmethyl-3-trifluoromethoxy-benzamide p this title from / V- (5-chloro-2- ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-3-trifluoromethoxy-benzamide (Compound C-1) under the same conditions as for Compound B-2.
LCMS: m / z 534 [M + H] + H PLC retention time: 0.54 min (analysis condition A) [Example 149] Compound C-3 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4- (4-isopropyl-p-piperazin-1-methyl) -3-trifluoromethoxy-benzamide The title compound was synthesized from N- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-3-trifluoromethoxy-benzamide (Compound C-1) under the same conditions as for the Compound B-3.
LCMS: m / z 562 [M + H] + HPLC retention time: 0.56 min (analysis condition A) [Example 150] Compound C-4 / V- (5-chloro-2-ethanesulfonyl-benzin-4-r4- (tetrahydro-pyran-4-yl) -piperazin-1-ylmethyl-3-trifluoromethoxy-benzamide The title compound was synthesized from A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-3-trifluoromethoxy-benzamide (Compound C-1) under the same conditions as for the Compound B-4.
LCMS: m / z 604 [M + H] + H PLC retention time: 0.55 min (analysis condition A) [Example 151] (R) - (potassium f3-r (ferc-butoxycarbonyl) amino] pyrrolidin-1-methylmethyl-1-trifluoroborate K Potassium (bromomethyl) trifluoroborate (1.13 g, 5.64 mmol) was added to a solution of urea-butyl ester of (R) -pyrrolidin-3-yl-carbamic acid (1.00 g, 5.37 mmol) in THF (20 g). mi), followed by reflux for 17 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Then acetone (50 ml) and potassium carbonate (742 mg, 5.37 mmol) were added and the mixture was stirred at room temperature for one hour. This was filtered through Celite and the filtrate was concentrated under reduced pressure to yield the title compound as a crude product.
[Example 152] illmetiOther potassium trifluoroborate K The title compound was synthesized using (S) -pyrrolidin-3-yl-carbamic acid fer-butyl ester under the same conditions as for potassium (R) - (. {3 - [(ferc-butoxycarbonyl) amino] pyrrolidine - 1 - i l.}. Methyl) trifluo robora to.
[Example 153 Compound C-5 4 - ((R) -3-amino-pyrrolidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide The title compound was synthesized from 4-chloro-3-trifluoromethoxy-benzoic acid ethyl ester (Compound c 1) and (R) - (. {3- [3- (ferc-butoxycarbonyl) amino] pyrrolidin-1-yl} methyl) trifluoroborate under the same conditions as for Compounds c2, c3, c4 and C-1. However, the reaction was performed using S- Phos instead of X-Phos under the conditions as for Compound c2.
LCMS: m / z 520 [M + H] + H PLC retention time: 0.43 min (analysis condition A) [Example 154] Compound C-6 4 - ((S) -3-ami not-pyrol id i n-1-ylmethyl) - (5-chloro-2-ethanesulfon ji be ncin-3-trifluo rometoxi-benza mida The title compound was synthesized from 4-chloro-3-trifluoromethoxy-benzoic acid ethyl ester (Compound d) and (S) - (. {3- [3- (fer-butoxycarbonyl) amino] pyrrolidin-1-yl} methyl) trifluoroborate under the same conditions as for Compounds c2, c3, c4 and C-1. However, the reaction was performed using S-Phos instead of X-Phos under the conditions as for Compound c2.
LCMS: m / z 520 [M + H] + H PLC retention time: 0.43 min (analysis condition A) [Example 155] Compound c5 3-Trifluoromethoxy-4-vinyl-benzoic acid ester A mixture of 4-chloro-3-trifluoromethoxy-benzoic acid ethyl ester (Compound d, 1 g, 3.7 mmol), potassium vinyltrifluoroborate (1.5 g, 11 mmol), palladium acetate (167 mg, 0.74 g) was stirred. mmol), 2 ', 6'-dimethoxy-2- (dicyclohexylphosphino) biphenyl (61 1 mg, 1.5 mmol) and cesium carbonate (3.64 g, 11 mmol) in THF (8 ml) / water (4 ml). ) at 90 ° C for 18 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (DCM / hexane) to yield the title compound (935 mg, 97%) as a substance oily HPLC retention time: 3.13 min (E analysis condition) [Example 156] Compound c6 Ethyl ester 4- (1,2-dihydroxy-ethyl) -3-trifluoromethoxy-benzoic acid Ethyl ester of 3-trifluoromethoxy-4-vinylbenzoic acid (Compound c5, 55 mg, 0.21 mmol) was added to a mixture of AD-mix-a (manufactured by Aldrich) (330 mg) in t-butyl alcohol (1 ml). ) / water (1 ml) and the mixture was stirred at room temperature for two hours. Sodium sulfite (21 1 mg) was added to the reaction solution, followed by stirring for an additional hour. The reaction solution was extracted with ethyl acetate and the organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (56.7 mg, 92%) as a colorless solid.
H PLC retention time: 1.77 min (E analysis condition) [Example 157] Compound c7 4-Formyl-3-trifluoromethoxy-benzoic acid ethyl ester The title compound was synthesized from 4- (1, 2-dihydroxy-ethyl) -3-trifluoromethoxy-benzoic acid ethyl ester (Compound c6) under the same conditions as for Compound b30.
[Example 158] Compound c8 Ethyl ester of 4 - ((S) -3-tert-butoxycarbonylamino-piperidin-1-ylmethyl-3-trifluoromethoxy-benzoic acid The title compound was synthesized from 4-formyl-3-trifluoromethoxy-benzoic acid ethyl ester (Compound el) under the same conditions as for Compound b32. However, the reaction was carried out using (S) -1-piperidin-3-ylmethylcarbamic acid fer-butylester in place of (S) -1-pyrrolidin-2-ylmethylcarbamic acid-butylester.
[Example 159] Compound c9 Acid _ 4 - ((S) -3-te / c-butoxycarbonyllamino-piperidin-1-methylmethD-3-t r if I or methoxybenzoic acid i The title compound was synthesized from 4 - ((S) -3-tert-butoxycarbonylamino-piperidin-1-ylmethyl) -3-trifluoromethoxy-benzoic acid ethyl ester (Compound c8) under the same conditions as for Compound b3 .
[Example 160] Compound d 0 Acid tertiary butyl ester -1 - f4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethoxy-benzyl-piperidin-3-illcarbamic The title compound was synthesized from 4 - ((S) -3-tert-butoxycarbonylamino-piperidin-1-ylmethyl) -3-trifluoromethoxy-benzoic acid (Compound c9) using DCM instead of DMF under the same conditions as for Compound A-14.
[Example 161] Compound C-7 4 - ((S) -3-amino-piperidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide The title compound was synthesized from acid fer-butyl ester. { (S) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2- trifluoromethoxy-benzyl] -piperidin-3-yl} -carbamic (Compound c10) under the same conditions as for Compound B-1.
LCMS: m / z 534 [M + H] + HPLC retention time: 0.48 min (analysis condition A) [Example 162] Compound C-8 / V- (5-chloro-2-ethanesulfonyl-benzin-4 - ((S) -3-dimethylamino-piperidin-1-ylmethyl) -3-trifluoromethoxy-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide (Compound C -7) under the same conditions as for Compound B-2.
LCMS: m / z 562 [M + H] HPLC retention time: 0.51 min (analysis condition A) [Example 163] Compound C-9 4 - ((S) -3-aceti lamí no-piperidin-1-lmethyl) -A / - (5-chloro-2-ethansulfon jibe ncil) -3-trifl uoromethoxy-benzam ida The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-methylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide (Compound C -7) under the same conditions as for Compound B-7.
LCMS: m / z 576 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 164] Compound C-10 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -4 - ((S) -3-methanesulfonylamino-piperidin-1-methylmethyl) -3-trifluoromethoxy-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide (Compound C -7) under the same conditions as for Compound B-9.
LCMS: m / z 612 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 165] Compound C-1 1 / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-4 - ((S) -3-ureido- piperidin-1-methylmethyl) -benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide (Compound C -7) under the same conditions as for Compound B-1 1.
LCMS: m / z 577 [M + H] HPLC retention time: 0.50 min (analysis condition A) [Example 166] Compound C-12 4-((S) -3- (2-Amino-acetylamino) -piperidin-1-methylmethin-A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide (Compound C -7) under the same conditions as for Compound B-5.
LCMS: m / z 591 [M + H] + HPLC retention time: 0.43 min (analysis condition A) [Example 167] Compound c1 1 Ethyl ester of 4-r (S) -3- (ferc-butoxycarbonyl-methylal) - romethoxy-benzoic acid The title compound was synthesized from 4-formyl-3-trifluoromethoxy-benzoic acid ethyl ester (Compound c7) and methyl- (S) -piperidin-3-yl-carbamic acid tert-butyl ester using DCM as the solvent under the Same conditions as for Compound b32.
[Example 168] Compound d 2 Acid _ 4-f (S) -3- (fe / -c-bu toxic rbon il-methyl-am inol-piperid in-1-yl methyl I -3-trifluoromethoxy-benzoic acid The title compound was synthesized from 4 - [(S) -3- (ferc-butoxycarbonyl-methyl-amino) -piperidin-1-ylmethyl] -3-trifluoromethoxy-benzoic acid ethyl ester (Compound c 1 1) under the same conditions as for Compound b8, [Example 169] Compound c13 Acid tert-butyl ester -f4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethoxy-benzin-piperidin-3-yl) -methylcarbamic acid The title compound was synthesized from 4 - [(S) -3- (fer-butoxycarbonyl-methyl-amino) -piperidin-1-ylmethyl] -3-trifluoromethoxy-benzoic acid (Compound c12) under the same conditions as for Compound A-14.
[Example 170] Compound C-13 / V- (5-chloro-2-ethanesulfonyl-benzin-4 - ((S) -3-methylamino-piperidin-1-ylmethio-3-trifluoromethoxy-benzamide The title compound was synthesized from acid fer-butyl ester. { (S) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2- trifluoromethoxy-benzyl] -piperidin-3-yl} -methyl-carbamic (Compound c13) under the same conditions as for Compound B-1. LCMS: m / z 548 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 171] Compound c14 Ethyl ester 4 - ((R) -3-tert-butoxycarbonylamino-p -peridin-1 - The title compound was synthesized from 4-formyl-3-trifluoromethoxy-benzoic acid ethyl ester (Compound c7) and (R) -piperidin-3-yl-carbamic acid tert-butylester under the same conditions as for Compound b32.
[Example 172] Compound d 5 4 - ((R) -3-tert-Butoxycarbonylamino-piperidin-1-methyl) -3-trifluoromethoxy-benzoic acid The title compound was synthesized from 4 - ((R) -3-tert-butoxycarbonylamino-piperidin-1-methylmethyl) -3-trifluoromethoxy-benzoic acid ethyl ester (Compound c14) under the same conditions like for Compound b8, [Example 173] Compound c16 1-f4- (5-Chloro-2-ethanesulfonyl-) tert-butyl ester b il b in 2 ifl toxi-benzyl-piperidin-3-yl > -carbamic The title compound was synthesized from 4 - ((R) -3-tert-butoxycarbonylamino-piperidin-1-ylmethyl) -3-trifluoromethoxy-benzoic acid (Compound c15) using DCM instead of DMF under the same conditions as for Compound A-14.
[Example 174] Compound C-14 4 - ((R) -3-amino-piperidin-1-ylmethyl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluoromethoxy-benzamide The title compound was synthesized from acid fer-butyl ester. { (R) -1 - [4- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -2- trifluoromethoxy-benzyl] -piperidin-3-yl} -carbamic (Compound c16) under the same conditions as for Compound B-1.
LCMS: m / z 534 [M + H] + H PLC retention time: 0.47 min (analysis condition A) [Example 175] Compound C-15 4 - ((S) -3-aminomethyl-pyrrolidin-1-methylmethyl- / V- (5-chloro-2-ethanesulfon ji be ncin-3-trifluoromethoxy-benzamid a The title compound was synthesized from 4-formyl-3-trifluoromethoxy-benzoic acid ethyl ester (Compound c7) and (R) -1-pyrrolidin-3-ylmethylcarbamic acid tert-butyl ester under the same conditions as for Compounds c14, c15, c16 and C- 14.
LCMS: m / z 534 [M + H] HPLC retention time: 0.41 min (analysis condition A) [Example 176] Compound C-16 4 - ((R) -3-aminomethyl-pyrrolidin-1-i I methyl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-trifluo-romethoxy-benzemide The title compound was synthesized from 4-formyl-3-trifluoromethoxy-benzoic acid ethyl ester (Compound c7) and (S) -1-pyrrolidin-3-ylmethylcarbamic acid tert-butyl ester under the same conditions as for Compounds c14, c15, c16 and C-14.
LCMS: m / z 534 [M + H] + HPLC retention time: 0.40 min (condition of analysis A) [Example 177] Compound d 1 Ter-butyl ester _ of _ acid _ 4- (5-amino-4-ethoxycarbonyl-2-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid A mixture of 2-amino-4-chloro-5-trifluoromethylbenzoic acid ethyl ester (Compound b27, 1.07 g, 4.0 mmol), potassium (4-tert-butoxycarbonylpiperazin-1-yl) methyltrifluoroborate (1.71 g, 5.6 mmol), palladium acetate (44.9 mg, 0.2 mmol), X-Phos (191 mg, 0.4 mmol) and cesium carbonate (3.91 g, 12 mmol) in THF (40 mL) and water (20 mL) it was stirred at 90 ° C for three hours. The reaction solution was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by column chromatography on silica gel (ethyl acetate / hexane) to give the title compound (1.49 g, 86%) as a pale yellow solid.
LCMS: m / z 432 [M + H] + HPLC retention time: 0.75 min (condition of analysis A) [Example 178] Compound d2 4- (3-Amino-2-chloro-4-ethoxycarbonyl-6-triflu-trifluic acid or tert-butyl ester) - for the 1-carboxylic acid NCS (1.71 g, 13 mmol) was added to a solution of 4- (5-amino-4-ethoxycarbonyl-2-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid tert-butylester (Compound d1, 4.62 g , 1 1 mmol) in DMF (90 ml) and the mixture was stirred at 65 ° C for three hours. Water was added to the reaction mixture, followed by extraction with hexane / ethyl acetate = 1/1. The organic layer was then washed with brine and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography. (ethyl acetate / hexane) to yield the title compound (2.70 g, 54%) as a yellow solid.
LCMS: m / z 466 [M + H] + H PLC retention time: 1.01 min (analysis condition A) [Example 179] Compound d3 4- (2-chloro-4-ethoxycarbonyl-6-trifluoromethyl- butyl acid butyl ester) benzyl) -piperazine-1-carboxylic acid The title compound was synthesized from 4- (3-amino-2-chloro-4-ethoxycarbonyl-6-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid fer-t-butyl ester (Compound d2) under the same conditions as for Compound b31.
[Example 180] Compound d4 4- (4-Carboxy-2-chloro-6-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid tert-butylester The title compound was synthesized from 4- (2-chloro-4-ethoxycarbonyl-6-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound d3) under the same conditions as for Compound b8 .
[Example 181] Compound d5 7 ~ 4-f2-Chloro-4- (5-chloro-2-ethanesulfonyl-n-cyccarbamoyl) -6-trifluoromethyl-benzyl-piperazine-1-carboxylic acid e-butyl ester i The title compound was synthesized from 4- (4-carboxy-2-chloro-6-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound d4) under the same conditions as for Compound A -5.
[Example 182 Compound D-1 3-chloro-AM5-chloro-2-ethanesulfonyl-benzin-4-piperazin-1-ylmethyl-5-trifluoromethyl-beza The title compound was synthesized from urea-butylester of 4- [2-chloro-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -6-trifluoromethyl-benzyl] -piperazine-1-carboxylic acid (Compound d5) under the same conditions as for Compound B-57 .
LCMS: m / z 538 [M + H] + HPLC retention time: 0.58 min (analysis condition A) [Example 183] Compound D-2 chloro-2-ethanesulfonyl-benzin-4- (4-methyl-piperazin-1 - n luoromethyl-benzamide p this title from 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-5-trifluoromethyl-benzamide (Compound D-1) under the same conditions as for Compound B-2.
LCMS: m / z 552 [M + H] + H PLC retention time: 0.58 min (analysis condition A) [Example 184] Compound D-3 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl-4- (4-isopropyl-piperazin-1-ylmethyl) -5-trifluoromethyl-benzamide The title compound was synthesized from 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-5-trifluoromethyl-benzamide (Compound D-1) under the same conditions as for Compound B-3.
LCMS: m / z 580 [M + H] + HPLC retention time: 0.60 min (analysis condition A) [Example 185] Compound D-4 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl-4-r4- (tetrahydro-pyran-4-ih-piperazin-1-ylmethyl H-5-trifluoromethyl-benzamide) The title compound was synthesized from 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-5-trifluoromethyl-benzamide (Compound D-1) under the same conditions as for Compound B-4.
LCMS: m / z 622 [M + H] + HPLC retention time: 0.59 min (condition of Analysis A) [Example 186] Compound d6 2-amino-3-chloro-4-formyl-5-zoic acid acetic acid NCS (3.71 g, 14 mmol) was added to a solution of 2-amino-4-formyl-5-trifluoromethylbenzoic acid ethyl ester (Compound b30, 3.63 g, 14 mmol) in DMF (42 mL) and the mixture was stirred 70 ° C for 0.5 hour. Water (40 ml) was added, followed by extraction with TBME. The extract was dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (3.47 g, 85% ) as a yellow solid.
LCMS: m / z 296 [M + H] + HPLC retention time: 0.89 min (analysis condition A) [Example 187] Compound d7 Ethyl ester of 3-chloro-4-formyl-5-trifluoromethylbenzoic acid The title compound was synthesized from ethylester of 2-m and non-3-chloro-4-form i-5-trifluoromethyl benzoic acid (Compound d6) under the same conditions as for Compound b31.
[Example 188] Compound d8 Ethyl ester of 4 - ((R) -3-te-c-butoxycarbonylamino-pyrrolidin-1-methyl) -3-chloro-5-trifluoromethylbenzoic acid The title compound was synthesized from 3-chloro-4-formyl-5-trifluoromethylbenzoic acid ethyl ester (Compound d7) and (R) -pyrrolidin-3-yl-carbamic acid terebutyl ester under the same conditions as for Compound b32.
[Example 189] Compound d9 4- (IR) -3-tert-butoxycarbonylamino-Dirrolidin-1-ylmethyl) -3-chloro-5-trifluoromethyl benzoic acid The title compound was synthesized from 4 - ((R) -3-tert-butoxycarbonylamino-pyrrolidin-1-methylmethyl) -3-chloro-5-trifluoromethylbenzoic acid ethyl ester (Compound d8) under the same conditions as for the Compound b8.
[Example 190] Compound d10 7 ~ e / -c-butyl ester of acid. { (R) -1-r2-chloro-4- (5-chloro-2-ethanesulfonyl-benzylcarbamom-6-trifluoromethyl-benzyl-pyrrolidin-3-ylcarbamic The title compound was synthesized from 4 - ((R) -3-tert-butoxycarbonylamino-pyrrolidin-1-ylmethyl) -3-chloro-5-trifluoromethylbenzoic acid (Compound d9) under the same conditions as for Compound A -14.
[Example 191] Compound D-5 4 - ((Rl-3-amino-pyrrolidin-1-ylmethyl-3-chloro - / {- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide The title compound was synthesized from tert-butyl ester of acid. { (R) -1 - [2-Chloro-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -6-trifluoromethyl-benzyl] -pyrrolidin-3-yl} -carbamic (Compound d10) under the same conditions corresponding to Compound B-1.
LCMS: m / z 538 [M + H] + H PLC retention time: 0.51 min (analysis condition A) [Example 192] Compound D-6 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-dimethylamino-pyrrolidin-1-ylmethyl) -5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-pyrrolidin-1-methylmethyl) -3-chloro - / (5- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl) -benzamide (Compound D-5) under the same conditions as for Compound B-2.
LCMS: m / z 566 [M + H] + H PLC retention time: 0.57 min (analysis condition A) [Example 193] Compound D-7 4 - ((R) -3-acetylamino-pyrrolidin-1-ylmethyl) -3-chloro- / V- (5-chloro-2- ethansulfonylbenzyl) -5 trifluoromethyl benzamide The title compound was synthesized from 4 - ((R) -3-amino-pyrrolidin-1-ylmethyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl- benzamide (Compound D-5) under the same conditions as for Compound B-7.
LCMS: m / z 580 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 194] Compound D-8 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-methanesulfonylamino-pyrrolidin-1-ylmethyl) -5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-pyrrolidin-1-ylmethyl) -3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl- benzamide (Compound D-5) under the same conditions as for Compound B-9 However, the reaction was performed at 0 ° C instead of room temperature.
LCMS: m / z 616 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 195] Compound D-9 3-chloro-A / - (5-chloro-2-ethansulph nor l-benzyl) -5-trifluoromethyl-4 - ((R) -3-ureido-pyrrolidin-1-methylmethin-benzamide The title compound was synthesized from 4 - ((R) -3-amino-pyrrolidin-1-ylmethyl) -3-chloro - / (5- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl) -benzamide (Compound D-5) under the same conditions as for Compound B-1 1.
LCMS: m / z 581 [M + H] + H PLC retention time: 0.49 min (analysis condition A) [Examples 196 to 202] The following compounds of Table 6 were synthesized from 3-chloro-4-formyl-5-trifluoromethylbenzoic acid ethyl ester (Compound d7) and corresponding amines under the same conditions as for Compounds d8, d9, d 10 and D- 5. However, in the synthesis of D-1 1, chloroform was used instead of THF as solvent under the conditions corresponding to d8. [Table 6] [Example 203 Compound D-12 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl-4 - ((Rl-3-dimethylamino-piperidin-1-methylmethyl-5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-piperidin-1-ylmethyl) -3-chloro - / (5- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl) -benzamide (Compound D-1 1) under the same conditions as for Compound B-2.
LCMS: m / z 580 [M + H] + HPLC retention time: 0.59 min (condition of Analysis A) [Example 204] Compound D-13 4 - ((R) -3-acetylamino- 1 i -3-chloro-N- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-piperidin-1-ylmethyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl- benzamide (Compound D-1 1) under the same conditions as for Compound B-7.
LCMS: m / z 594 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 205] Compound D-14 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl-4 - ((R) -3-methanesulfonylamino-piperidin-1-ylmethyl) -5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3- amino-piperidin-1-ylmethyl) -3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide (Compound D-1 1) under the same conditions as for Compound B- 9.
LCMS: m / z 630 [M + H] + HPLC retention time: 0.64 min (analysis condition A) [Example 206] Compound D-15 3-chloro-A / - (5-chloro-2-ethansulfon-M-benzyl) -5-trifluoromethyl-4 - ((R) -3-ureido-piperidin-1-ylmethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-piperidin-1-methylmethyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5- trifluoromethyl-benzamide (Compound D-1 1) under the same conditions as for Compound B-1 1.
LCMS: m / z 595 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 207] Compound D-16 4-R (R) -3- (2-Amino-acetylamino) -piperidin-1-ylmethin-3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-piperidin-1-ylmethyl) -3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl- benzamide (Compound D-1 1) under the same conditions as for Compound B-5.
LCMS: m / z 609 [M + H] + HPLC retention time: 0.46 min (analysis condition A) [Example 208] Compound D-19 chloro-2-ethanesulfonyl-benzyl-4 - ((S) -3-dimethylamino- metin-5-trifluoromethyl-benzamide title t from 4 - ((S) -3-amino-piperidin-1-ylmethyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide ( Compound D-18) under the same conditions as for Compound B-2.
LCMS: m / z 580 [M + H] + HPLC retention time: 0.59 min (condition of Analysis A) [Example 209] Compound D-20 4 - ((S) -3-acetylamino- -1-methylmethyl) -3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-methyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl -benzamide (Compound D-18) under the same conditions as for Compound B-7.
LCMS: m / z 594 [+ H] + HPLC retention time: 0.55 min (analysis condition A) [Example 210] Compound D-21 3-clo ro- / V- (5-chloro-2-ethanesulfon i l-be ncih-4 - ((So goal nsulfo nilamino-piperidin-1-ylmetiD-5-trifluoro metí l-benza mida The title compound was synthesized from 4 - ((S) -3- amino-piperidin-1-ylmethyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide (Compound D-18) under the same conditions as for Compound B-9 .
LCMS: m / z 630 [M + H] + HPLC retention time: 0.64 min (analysis condition A) [Example 21 1] Compound D-22 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl-5-trifluoromethyl-4 - ((S) -3-ureido-piperidin-1-ylmethyl-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-methylmethyl) -3-chloro - / (5- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl) -benzamide (Compound D-18) under the same conditions as for Compound B-1 1.
LCMS: m / z 595 [M + H] + HPLC retention time: 0.52 min (analysis condition A) [Example 212] Compound D-23 4-r (S) -3- (3-amino-propionylamino) -piperidn-1-methylmethyl-3-chloro-A / - (5- chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl- benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-methylmethyl) -3-chloro - / (5- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl) -benzamide (Compound D-18) and 3- tert-butoxycarbonylamino-propionic acid under the same conditions as for Compound B-5.
LCMS: m / z 623 [M + H] H PLC retention time: 0.45 min (analysis condition A) [Example 213] Compound D-24 4-r (S) -3- (2-amino-2-methyl-propionylamino) -piperidin-1-methylmethyl-3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl-5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) -3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl- benzamide (Compound D-18) under the same conditions as for Compound B-33.
LCMS: m / z 637 [M + H] HPLC retention time: 0.48 min (analysis condition A) [Example 214] Compound D-25 4-r (S) -3- (2-amino-acetylamino) -piperidin-1-methylmethyl-3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzin-5-trifluoromethyl-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl- benzamide (Compound D-18) under the same conditions as for Compound B-5.
LCMS: m / z 609 [M + H] + HPLC retention time: 0.46 min (analysis condition A) [Example 215] Composite e1 2-Amino-3-bromo-4-formyl-5-trifluoromethylbenzoic acid ester NBS (639 mg, 2.29 mmol) was added to a solution of ethyl ester of 2-amino-4-formyl-5-trifluoromethylbenzoic acid (Compound b30, 300 mg, 1.15 mmol) in DMF (3 mL) and the mixture was stirred at 50 ° C for one hour. The reaction solution was extracted with ethyl acetate and the extract was washed with brine and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (342 mg, 87%).
LCMS: m / z 340 [M + H] + HPLC retention time: 0.87 min (analysis condition A) [Example 216] Compound e2 Used 3-bromo-4-formyl-5-trifluoromethylbenzoic acid The title compound was synthesized from 2-amino-3-bromo-4-formyl-5-trifluoromethylbenzoic acid ethyl ester.
(Compound e1) under the same conditions as for Compound b31.
[Example 217] Compound e3 Ethyl ester of 3-bromo-4-r (S) -3- (ferc-butoxycarbonylamino- methyl) -pyrrolidin-1-methylmethin-5-trifluoromethylbenzoic acid The title compound was synthesized from 3-bromo-4-formyl-5-trifluoromethylbenzoic acid ethyl ester (Compound e2) and (R) -1-pyrrolidin-3-ylmethylcarbamic acid fer-butyl ester under the Same conditions as for Compound b32.
[Example 218] Compound e4 3-bromo-4-r (S) -3- (tert-butoxycarbonylamino-methyl) -pyrrolidin-1-methylmethyl-5-trifluoromethylbenzoic acid The title compound was synthesized from 3-bromo-4 - [(S) -3- (1-tert-butoxycarbonylamino-methyl) -pyrrolidin-1-ylmethyl] -5-trifluoromethylbenzoic acid ethyl ester (Compound e3) under the same conditions like for Compound b8 [Example 219] Compound e5 acid butylester. { (S) -1-f2-bromo-4- (5-chloro-2-ethanesulfonyl- benzylcarbamoyl) -6-trifluoromethyl-benzyl-pyrrolidin-3-Mmethyl > - carbamic The title compound was synthesized from 3-bromo-4 - [(S) -3- (terebu toxic rbonylamino-methyl) -pi rro lid in-1-ylmethyl] -5-trifluoromethylbenzoic acid (Compound e4) under the same conditions as for Compound A-14.
[Example 220] Compound E-1 4 - ((S) -3-aminomethyl-pyrrolidin-1-ylmethin-3-bromo - / \ / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethyl-benzamide The title compound was synthesized from acid tert-butyl ester. { (S) -1- [2-bromo-4- (5-chloro-2-ethanesulfonyl-be nci lea rbamoyl) -6-trif luoromet I-be ncil] - pyrro lid i h -3-ylmethyl} -carbamic (Compound e5) under the same conditions as for Compound B-1.
LCMS: m / z 596 [M + H] + Hretention time: 0.43 min (analysis condition A) [Examples 221 to 223] The following compounds of Table 7 were synthesized from 3-bromo-4-formyl-5-trifluoromethylbenzoic acid ethyl ester (Compound e2) using corresponding cyclic amines under the same conditions as for Compounds e3, e4, e5 and E- 1 .
[Table 7] [Example 224] Compound e6 Acid 3-b ro mo-4-form i l-5-triflu promised l-benzoic [Compound 193] The title compound was synthesized from 3-bromo-4-formyl-5-trifluoromethylbenzoic acid ethyl ester (Compound e2) under the same conditions as for Compound b8.
[Example 225] Composed on 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-formyl-5-trifluoromethyl-benzamide The title compound was synthesized from 3-bromo-4-formyl-5-trifluoromethylbenzoic acid (Compound e6) under the same conditions as for Compound A-14.
[Example 226] Compound e8 Acid tert-butylester. { (R) -1-R2-bromo-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoy-6-trifluoromethyl-benzyl-1-piperidin-3-yl) -carbic The title compound was synthesized from 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-formyl-5-trifluoromethyl-benzamide (Compound e7) and acid fer-butyl ester ( R) -piperidin-3-yl-carbamic acid under the same conditions as for Compound b32. However, chloroform was used instead of THF as the solvent.
[Example 227] Compound E-5 4 - ((R) -3-amino-piperidin-1-ylmethin-3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzin-5-trifluoromethyl-benzamide The title compound was synthesized from acid urea-butylester. { (R) -1 - [2-Bromo-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -6-trifluoromethyl-benzyl] -piperidin-3-yl} -carbamic (Compound e8) under the same conditions as for Compound B-57.
LCMS: m / z 596 [M + H] + Hretention time: 0.58 min (condition of Analysis A) [Examples 228 to 230] The following compounds of Table 8 were synthesized from 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-formyl-5-trifluoromethyl-benzamide (Compound e7) using the corresponding cyclic amines under the same conditions as for Compounds e8 and E-5.
[Table 8] [Example 231] Compound f1 4-bromo-2-nitro-5-trifluoromethoxy-benzoic acid A solution of 2-nitro-5-trifluoromethoxy-benzoic acid (25.3 g, 0.10 mol) in concentrated sulfuric acid (75 ml) was warmed at 80 ° C and NBS (18 g, 0.10 mol) was added in three portions at intervals. 15 min. After stirring at 80 ° C for two hours, N BS (9.0 g, 0.050 mol) and concentrated sulfuric acid (25 ml) were added and the mixture was stirred at 80 ° C for an additional three hours. The reaction mixture was cooled to room temperature and then added to ice water and the solid filtered. This was washed with H2O and methanol and then H20 / methanol = 5/1 (120 ml) was added, followed by stirring at 0 ° C for 30 minutes. The solid was collected by filtration, washed with H20 / methanol = 5/1 and dried to yield the title compound as a crude product.
[Example 232] Compound f2 Ethyl ester of 4-bromo-2-nitro-5-trifluoromethoxy-benzoic acid The title compound was synthesized from 4-bromo-2-nitro-5-trifluoromethoxy-benzoic acid (Compound f1) under the same conditions as for Compound b1.
[Example 233] Compound f3 Tertiary butyl ester of 4- (4-ethoxycarbonyl-5-nitro-2- pe-1 -carboxylic acid) The title compound was synthesized from 4-bromo-2-nitro-5-trifluoromethoxy-benzoic acid ethyl ester (Compound f2) under the same conditions as for Compound b2.
[Example 234] Compound f4 4- (5-Amino-4-ethoxycarbonyl-2-trifluoromethoxy-benzyl-piperazine-1-carboxylic acid tert -butylester A saturated aqueous solution of ammonium chloride (12 mL) was added to a suspension of 4- (4-ethoxycarbonyl-5-nitro-2-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound f3, 1.2 g, 2.5 mol) and iron (702 mg, 13 ol) in 2-PrOH (12 ml) and the mixture was stirred at 100 ° C for 1.5 hours. hours. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (760 mg, 68%) in form of a frothy substance of yellow color.
LCMS: m / z 448 [M + H] + H PLC retention time: 2.16 min (condition of analysis C) [Example 235] Compound f5 4- (3-Amino-2-chloro-4-ethoxycarbonyl-6-trifluoromethoxy-benzyl-piperazine-1-carboxylic acid terebutyl ester title post from 4- (5-amino-4-ethoxycarbonyl-2-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid fer-butylester (Compound f4) under the same conditions as for Compound d2.
[Example 236] Compound f6 butyl ester of 4- (2-chloro-4-ethoxycarbonyl-6-) trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid The title compound was synthesized from 4- (3-amino-2-chloro-4-ethoxycarbonyl-6-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid (Compound f5) acid-butylester under the same conditions as for Compound b31.
[Example 237] Compound f7 4- (4-carboxy-2-chloro-6-trifluoromethoxy-benzyl-piperazine-1-carboxylic acid tert -butylester The title compound was synthesized from 4- (2-chloro-4-ethoxycarbonyl-6-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid tert-butylester (Compound f6) under the same conditions as for Compound b3 .
[Example 238] Compound f8 7 ~ e / ~ c-butyl ester of 4-r2-chloro-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -6-trifluoromethoxy-benzyl-piperazine na-1-carboxylic acid The title compound was synthesized from 4- (4-carboxy-2-chloro-6-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid fer-butyl ester (Compound f7) under the same conditions as for the Compound A-14.
[Example 239] Compound F-1 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl-4-piperazin-1-ylmethyl-5-trifluoromethoxy-benzamide) The title compound was synthesized from 4- [2-chloro-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -6-trifluoromethoxy-benzyl] -piperazine-1-carboxylic acid tert -butylester (Compound f8 ) under the same conditions as for Compound B-1.
LCMS: m / z 554 [M + H] + HPLC retention time: 1.52 min (condition of analysis D) [Example 240] Compound F-2 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4- (4-methyl-piperazin-1-ylmethyl) -5-trifluoromethoxy-benzamide The title compound was synthesized from 3-chloro-N-. { 5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-5-trifluoromethoxy-benzamide (Compound F-1) under the same conditions as for Compound B-2.
LCMS: m / z 568 [M + H] + HPLC retention time: 1.55 min (analysis condition D) [Example 241] Compound F-3 3-chloro-A / - (5-chloro-2-ethanesulfon-1-benzyl) -4- (4-isopropyl-1-piper-1-ylmethyl) -5-trifluoromethoxy-benzamide The title compound was synthesized from 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmet-5-trifluoromethoxy-benzamide (Compound F-1) under the same conditions as for Compound B-3.
LCMS: m / z 596 [M + H] + HPLC retention time: 1.65 min (analysis condition D) [Example 242] Compound F-4 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzin-4-r4- (tetrahydro-pyran-4-ih-piperazin-1-ylmethyl-5-trifluoromethoxy-benzamide The title compound was synthesized from 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-5-trifluoromethoxy-benzamide (Compound F-1) under the same conditions as for Compound B-4.
LCMS: m / z 638 [M + H] + H PLC retention time: 1.58 min (analysis condition D) [Example 243] Compound f9 4- (3-Amino-2-bromo-4-ethoxycarbonyl-6-) -1-carboxylic acid tert-butyl ester Bromide (505 ml, 9.8 mmol) was added to a suspension of 4- (5-amino-4-ethoxycarbonyl-2-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid fer-butyl ester (Compound f4, 880 mg, 2.0 mmol) and iron (549 mg, 9.8 mmol) in chloroform and the mixture was stirred at 60 ° C for one hour. The reaction solution was diluted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was dissolved in DCM (10 mL) and Boc20 (430 mg, 2.0 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (195 mg, 19%) as an oily substance LCMS: m / z 526 [M + H] + H PLC retention time: 2.26 min (analysis condition C) [Example 244] Compound F-5 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-5- trifluoromethoxy-benzamide The title compound was synthesized from 4- (3-amino-2-bromo-4-ethoxycarbonyl-6-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid terebutyl ester (Compound f9) under the same conditions as for Compounds f 6, f7, f8 and F-1.
LCMS: m / z 598 [M + H] HPLC retention time: 0.56 min (analysis condition A) [Example 245] Compound f10 2-Nitro-5-trifluoromethoxy-4-vinyl-benzoic acid ethyl ester The title compound was synthesized from 4-bromo-2-nitro-5-trifluoromethoxy-benzoic acid ethyl ester (Compound f2) under the same conditions as for Compound b28. [Example 246] Compound f1 1 2-Amino-5-trifluoromethoxy-4-vinyl-benzoic acid ethyl ester A saturated aqueous solution of ammonium chloride (1.5 ml) and powdered zinc (167 mg, 2.6 mmol) was added to a solution of 2-nitro-5-trifluoromethoxy-4-vinylbenzoic acid ethyl ester (Compound f 10 , 156 mg, 0.51 mmol) in 2-PrOH (1.5 mi) and the mixture was stirred at 80 ° C for one hour. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (DCM / hexane) to yield the title compound (140 mg, quant.) As a solid. of brown color. 1 H-NMR (300 MHz, CDCl 3) d: 7.73 (1 H, s), 6.86 (1 H, dd, J = 17.7, 11.2 Hz), 6.82 (1 H, s), 5.81 (1 H, d, J = 17.7 Hz), 5.76 (2H, brs), 5.45 (1 H, d, J = 11.2 Hz), 4.34 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). [Example 247] Compound f12 Ethyl ester of 2-amino-4- (1,2-dihydroxy-ethyl) -5-trifluoromethoxy acid The title compound was synthesized from 2-amino-5-trifluoromethoxy-4-vinyl-benzoic acid ethyl ester (Compound F1 1) under the same conditions as for Compound b29. [Example 248] Compound f13 Ethyl ester of 2-amino-4-formyl-5-trifluoromethoxy-benzoic acid The title compound was synthesized from 2-amino-4- (1, 2-dihydroxy-ethyl) -5-trifluoromethoxy-benzoic acid ethyl ester (Compound f 12) under the same conditions as for Compound b30.
[Example 249] Compound f 14 Ethyl ester of 2-amino-3-chloro-4-formyl-5-trifluoromethoxy-benzoic acid The title compound was synthesized from 2-amino-4-formyl-5-trifluoromethoxy-benzoic acid ethyl ester (Compound f 13) under the same conditions as for Compound d6. [Example 250] Compound f15 3-Chloro-4-formyl-5-trifluoromethoxy-benzoic acid ester The title compound was synthesized from 2-am i non-3-chloro-4-form i-5-trifluoromethoxy-benzoic acid ethyl ester (Compound f14) under the same conditions as for Compound b31.
[Example 251] Compound f 16 Ethyl ester 4 - ((R) -3-tert-butoxycarbonylamino-Dyrrolidin-1-methylmethin-3-chloro-5-trifluoromethoxy-benzoic acid The title compound was synthesized from 3-chloro-4-formyl-5-trifluoromethoxy-benzoic acid ethyl ester (Compound f15) and (R) -pyrrolidin-3-yl-carbamic acid terebutyl ester under the same conditions as for Compound b32.
[Example 252 Compound f17 4 - ((Rl-3-te / c-butoxycarbonylamino-pyrrolidin-1-methylmethyl) -3-chloro-5-trifluoromethoxy-benzoic acid The title compound was synthesized from 4 - ((R) -3-tert-butoxycarbonylamino-pyrrolidin-1-methylmethyl) -3-chloro-5-trifluoromethoxy-benzoic acid ethyl ester (Compound f 16) under the same conditions as for Compound b8.
[Example 253] Compound f18 ((R) -1-R2-Chloro-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl-6-trifluoromethoxy-benzyl-pyrrolidin-3-yl) -carbamic acid tert-butylester The title compound was synthesized from 4 - ((R) -3-tert-bu toxic rbonilam and non-pyrro lid i n-1-ylmethyl) -3-chloro-5-trifluoromethoxy-benzoic acid (Compound f17) under the same conditions as for Compound A-14.
[Example 254] Compound F-6 4 - ((R) -3-Amino-pyrrolidin-1-ylmethyl) -3-chloro - / \ / - (5-chloro-2-ethanesulfonyl-benzin-5-trifluoromethoxy-benzamide The title compound was synthesized from acid fer-butyl ester. { (R) -1 - [2-Chloro-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -6-trifluoromethoxy-benzyl] -pyrrolidin-3-yl} -carbamic (Compound f 18) under the same conditions corresponding to Compound B-1.
LCMS: m / z 554 [M + H] + HPLC retention time: 0.49 min (analysis condition A) [Examples 255 to 259] The following compounds of Table 9 were synthesized from 3-chloro-4-formyl-5-trifluoromethoxy-benzoic acid ethyl ester (Compound f15) and corresponding amines under the same conditions as for Compounds f16, f17, f18 and F-6 However, chloroform was used as solvent under the conditions as for Compound f 16 in the synthesis of Compounds F-7 and F-8 and DCM was used as solvent under the conditions as for Compound f 16 in the synthesis of the Compounds F-9, F-15 and F-16. Additionally, DCM was used as a solvent under the same conditions for Compound f 18 in the synthesis of Compounds F-16.
[Table 9] [Example 260] Compound F-10 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl-4 - ((S) -3-dimethylamino-piperidin-1-ylmethyl-5-trifluoromethoxy-benzamide 5 The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) -3-chloro - / {- (5-chloro-2-ethanesulfonyl-benzyl) -5- trifluoromethoxy-benzamide (Compound F-9) under the same conditions as for Compound B-2.
LCMS: m / z 596 [M + H] + HPLC retention time: 0.58 min (condition of 15 analysis A) [Example 261] Compound F-12 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((S) -3-methanesulfonylamino-piperidin-1-ylmethyl) -5-trifluoromethoxy-benzamide The title compound was synthesized from 4 - ((S) -3- amino-piperidin-1-methylmethyl) -3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide (Compound F-9) under the same conditions as for Compound B-9.
LCMS: m / z 646 [M + H] + HPLC retention time: 0.59 min (analysis condition A) [Example 262] Compounds F-1 1 and F-13 were synthesized from 4 - ((S) -3-amino-piperidin-1-ylmethyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) ) -5-trifluoromethoxy-benzamide (Compound F-9) under the same conditions as for Compound B-1 1.
Compound F-1 1 4 - ((Sl-3-acetylamino-piperidin-1-ylmethyl-3-chloro-N- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide LCMS: m / z 610 [M + H] HPLC retention time: 0.54 min (condition of analysis A) Compound F-13 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzin-5-trifluoromethoxy-4 - ((S) -3-ureido-piperidin-1-ylmethi-benzamide LCMS: m / z 61 1 [M + H] HPLC retention time: 0.52 min (analysis condition A) [Example 263] Compound F-14 4-r (S) -3- (2-Amino-acetylamino) -piperidin-1-ylmethyl-3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide The title compound was synthesized from 4 - ((S) -3-amino-piperidin-1-methylmethyl) -3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy- benzamide (Compound F-9) under the same conditions as for Compound B-5.
LCMS: m / z 625 [M + H] + HPLC retention time: 0.44 min (analysis condition A) [Example 264] Compound g 1 3-bromo-4-methyl-benzoic acid ester The title compound was synthesized from 3-bromo-4-methyl-benzoic acid under the same conditions as for Compound b1.
[Example 265] Compound g2 3-bromo-4-bromomethyl-benzoic acid ester The title compound was synthesized from 3-bromo-4-methyl-benzoic acid ethyl ester (Compound g1) under the same conditions as for Compound b6.
[Example 266] Compound g3 4- (2-Bromo-4-ethoxycarbonyl-benzyl) -pjperazine-1-carboxylic acid tert-butylester Ferric-butyl ester of piperazine-1-carboxylic acid (2.6 g, 14.3 mmol) was added to a mixture of 3-bromo-4-bromomethyl) -benzoic acid ethyl ester (Compound g 2, 2.28 g, 7.08 mmol) in THF and The mixture was stirred at 75 ° C for three hours. After the reaction solution was cooled to room temperature, it was added water, followed by extraction with dichloromethane. The organic layer was washed three times with water and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the residue obtained after concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (1.2 g, 40%). ).
LCMS: m / z 427 [M + H] + HPLC retention time: 1 .13 min (E analysis condition) [Example 267] Compound g4 4- (2-Bromo- -carboxy-benzyl-piperazine-1-carboxylic acid terebutyl ester) The title compound was synthesized from 4- (2-bromo-4-ethoxycarbonyl-benzyl) -piperazine-1-carboxylic acid tert-butylester (Compound g 3) under the same conditions as for Compound b3.
[Example 268] Compound g5 Terebutyl ester of 4-f2-bromo-4- (5-chloro-2-ethanesulfonyl-be nci lea rbamoi P-be n cill-pi pe ratio a-1-carboxylic acid The title compound was synthesized from 4- (2-bromo-4-carboxy-benzyl) -piperazine-1-carboxylic acid fer-butyl ester (Compound g4) under the same conditions as for Compound A-14.
[Example 269] Compound G-1 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl-4-piperazin-1-ylmethyl-benzamide) The title compound was synthesized from 4- [2-bromo-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -benzyl] -piperazine-1-carboxylic acid fer-t-butyl ester (Compound g 5) under the same conditions as for Compound B-1.
LCMS: m / z 514 [M + H] H PLC retention time: 1 .18 min (analysis condition D) [Example 270] Compound G-2 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4- (4-methyl-piperazin-1 - ilmetin-benzamide The title compound was synthesized from 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-benzamide (Compound G-1) under the same conditions as for the Compound B-2.
LCMS: m / z 528 [M + H] HPLC retention time: 1.28 min (analysis condition D) [Example 271] Compound G-3 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4- (4-isopropyl-piperazin-1-ylmethin-benzamide) The title compound was synthesized from 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-benzamide (Compound G-1) under the same conditions as for the Compound B-3.
LCMS: m / z 556 [M + H] H PLC retention time: 0.51 min (analysis condition A) [Example 272] Compound G-4 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl-4-r4- (tetrahydro-pyran-4-ih-piperazin-1-methylmethin-benzamide The title compound was synthesized from 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-benzamide (Compound G-1) under the same conditions as for Compound B-4.
LCMS: m / z 598 [M + H] + H PLC retention time: 0.50 min (analysis condition A) [Example 273] Compound g6 Eti leste r of 3-bromo-4 - ((R) -3-te / ~ c-butoxycarbonylamino-pyrrolidin-1-ylmethyl-benzoic acid p sto title from ethilester of 3-bromo-4-bromomethyl-benzoic acid (Compound g2) and tert-butyl ester of (R) -pyrrolidin-3-yl-carbamic acid under the same conditions as for Compound b7.
[Example 274] Compound g7 Acid _ 3-bromo-4 - ((R) -3-tert-butoxycarbonylamino-pyrrolidin-1 - Imethyl-benzoic acid An aqueous solution of 6N sodium hydroxide (3 ml) was added to a solution of 3-bromo-4 - ((R) -3-tert-butoxycarbonylamino-pyrrolidin-1-ylmethyl) -benzoic acid ethyl ester (Compound g6, 1.224 g, 2.9 mmol) in EtOH (14.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized by the addition of an aqueous solution of hydrochloric acid. The aqueous layer was then extracted with ethyl acetate and the organic layer was collected, washed with saturated saline solution and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was then concentrated under reduced pressure to yield a crude product of the title compound.
[Example 275] Compound g8 F (R) -1-r2-bromo-4- (5-chloro-2-ethanesulfonyl-) tert-butylester benzylcarbamoyl-benzyl-pyrrolidin-3-ill-carbamic The title compound was synthesized from 3-bromo-4 - ((R) -3-tert-butoxycarbonylamino-pyrrolidin-1-ylmethyl) -benzoic acid (crude compound g7) under the same conditions as for Compound A- 1 .
[Example 276] Compound G-5 4 - ((R) -3-amino-pyrrolidin-1-methylmethyl) -3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl-benzamide The title compound was synthesized from acid fer-butyl ester. { (R) -1 - [2-Bromo-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -benzyl] -pyrrolidin-3-yl} -carbamic (Compound g8) under the same conditions as for Compound B-1.
LCMS: m / z 514 [M + H] + H PLC retention time: 0.39 min (analysis condition A) [Example 277] Compound G-6 3-bromo - / \ / - (5-chloro-2-ethanesulfonyl-benzin-4 - ((R) -3-dimethylamino-pyrrolidin-1-ylmethyl-benzamide The title compound was synthesized from 4 - ((R) -3 amin or -pyrro lidin-1-methylmethyl) -3-b-romo-A / - (5-chloro-2-ethanesulfonyl-benzyl) - benzamide (Compound G-5) under the same conditions corresponding to Compound B-2.
LCMS: m / z 542 [M + H] + HPLC retention time: 0.44 min (analysis condition A) [Example 278] Compound G-7 4 - ((R) -3-acetylamino-pyrrolidin-1-lmetiD-3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzD-benzamide The title compound was synthesized from 4 - ((R) -3-amine-pyrrolidin-1-ylmethyl) -3-bromo- / (-5-chloro-2-ethanesulfonylbenzyl-benzamide (Compound G -5) under the same conditions as for Compound B-7.
LCMS: m / z 556 [M + H] + HPLC retention time: 0.47 min (analysis condition A) [Example 279] Compound G-8 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-methanesulfonylamino-pyrrolidin-1-ylmethyl-benzamide The title compound was synthesized from 4 - ((R) -3-amino-pyrrolidin-1-ylmethyl) -3-bromo- / / (5-chloro-2-ethanesulfonyl-benzyl) -benzamide (Compound G-5) under the same conditions as for Compound B-9.
LCMS: m / z 592 [M + H] + H PLC retention time: 0.49 min (analysis condition A) [Example 280] Compound G-9 3-bromo- / V- (5-chloro-2-ethanesulfon i-benzyl) -4 - ((R) -3-methylamido non-pyrro lidin-1-methylmethyl-benzamide The title compound was synthesized from 3-bromo-4-bromomethyl-benzoic acid ethyl ester (Compound g2) under the same conditions as for Compounds g6, g7, g8 and G-5. However, the reaction was carried out using methyl- (R) -pyrrolidin-3-yl-carbamic acid fer-butylester in place of (R) -pyrrolidin-3-yl-carbamic acid fer-butylester under the conditions as for Compound g6.
LCMS: m / z 528 [M + H] + H PLC retention time: 0.42 min (analysis condition A) [Example 281] Compound G-10 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzin-4-f (R) -3- (methanesulfonyl-methyl-amino) -pyrrolidin-1-ylmethyl-1-benzamide The title compound was synthesized from 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((R) -3-methylamino-pyrrolidin-1-methyl) -benzamide (Compound G-9) under the same conditions as for Compound B-9.
LCMS: m / z 606 [M + H] + H PLC retention time: 0.51 min (analysis condition A) [Example 282] Compound G-1 1 3-chloro-AM5-chloro-2-ethanesulfonyl-benzin-4-piDerazin-1-methylmethyl-benzamide The title compound was synthesized from 3-chloro-4-methyl-benzoic acid ethyl ester under the same conditions as for Compounds g2, g3, g4, g5 and G-1. However, the reaction was carried out using an aqueous solution of 6N sodium hydroxide instead of potassium hydroxide at room temperature under the conditions as for Compound g4.
LCMS: m / z 470 [M + H] + H PLC retention time: 0.47 min (analysis condition A) [Example 283] Compound G-12 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4- (4-methyl-piperazin-1-ylmethyl-benzamide) The title compound was synthesized from 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-benzamide (Compound G-1) under the same conditions as for Compound B-2.
LCMS: m / z 484 [M + H] + HPLC retention time: 0.49 min (analysis condition A) [Example 284] Compound G-13 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4- (4-isopropyl-piperazin-1-methylmethyl) -benzamide The title compound was synthesized from 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-benzamide (Compound G-1) under the same conditions as for Compound B-3.
LCMS: m / z 512 [M + H] + H PLC retention time: 0.51 min (analysis condition A) [Example 285] Compound G-14 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4- [4- (tetdro-pyran-4- P a The title compound was synthesized from 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-benzamide (Compound G-1 1) under the same conditions as for Compound B-4.
LCMS: m / z 554 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 286] Compound G-15 3 5-d i bromo- / V- (5-cl or ro-2-ethanesulfon i-benzyl) -4-p i pe ratio-1-methylmethylbenzamide Title compound from 3,5-dibromo-4-methyl-benzoic acid methylester under the same conditions as for Compounds g2, g3, g4, g5 and G-1. However, the reaction was carried out using an aqueous solution of 6N sodium hydroxide instead of potassium hydroxide at room temperature under the conditions as for Compound g4.
LCMS: m / z 592 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 287] Compound G-16 3. 5-dibromo- / V- (5-chloro-2-ethanesulfonyl-benzyl-4- (4-methyl-piperazin-1-methyl-benzamide The title compound was synthesized from 3,5-dibromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-benzamide (Compound G-15) under the same conditions as for Compound B-2.
LCMS: m / z 606 [M + H] + H PLC retention time: 0.54 min (analysis condition A) [Example 288] Compound G-17 3. 5-dibromo- / V- (5-chloro-2-ethanesulfonyl-benzM) -4- (4-isopropyl-piperazin-1-ylmethyl-benzamide) The title compound was synthesized from 3,5-dibromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-ylmethyl-benzamide (Compound G-15) under the same conditions as for Compound B-3.
LCMS: m / z 634 [M + H] + H PLC retention time: 0.56 min (analysis condition A) [Example 289] Compound G-18 3. 5-dibromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -4-y4- (tetdro-pyran-4-yl) -piperazin-1-ylmethyl-benzamide The title compound was synthesized from 3,5-dibromo- / / (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-methylmethyl-benzamide (Compound G-15) under the same conditions as for Compound B-4.
LCMS: m / z 676 [M + H] + H PLC retention time: 0.54 min (analysis condition A) [Example 290] Compound h 1 3-bromo-5-trifluoromethoxy-benzoic acid ester The title compound was synthesized from 3-bromo-5-trifluoromethoxy-benzoic acid under the same conditions as for Compound b1.
[Example 291] Compound h2 7 ~ erc-butyl ester of 4- (3-ethoxycarbonyl-5-trifluoromethoxy-benzyl-piperazine-1-carboxylic acid) The title compound was synthesized from 3-bromo-5-trifluoromethoxy-benzoic acid ethyl ester (Compound h 1) under the same conditions as for Compound b2.
[Example 292] Compound h3 7 ~ 4- (3-carboxy-5-trifluoromethoxy-benzyl) -1 -carboxylic acid erc-butylester The title compound was synthesized from 4- (3-ethoxycarbonyl-5-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid fer-t-butyl ester (Compound h2) under the same conditions as for Compound b3.
[Example 293] Compound h4 4-R3- (5-Chloro-2-ethanesulfonyl-benzylcarbamom-5-trifluoromethoxy-benzyl-piperazine na-1-carboxylic acid tert-butylester The title compound was synthesized from 4- (3-carboxy-5-trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid terebutyl ester (Compound h3) under the same conditions as for Compound A-14.
[Example 294] Compound H-1 / \ M5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-methylmethyl-5-trifluoromethoxy-benzamide The title compound was synthesized from 4- [3- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -5-trifluoromethoxy-benzyl] -piperazine-1-carboxylic acid fer-butyl ester (Compound h4) under the same conditions as for Compound B-1.
LCMS: m / z 520 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 295] Compound H-2 / VM5-Chloro-2-ethanesulfonyl-benzyl-3- (4-methyl-p-piperazin-1-ylmethyl-P-5-trifluoromethoxy-benzamide) The title compound was synthesized from A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-methylmethyl-5-trifluoromethoxy- benzamide (Compound H-1) under the same conditions as for Compound B-2.
LCMS: m / z 534 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 296] Compound H-3 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -3- (4-isopropyl-p-eperazin-1-ylmethyl-5-trifluoromethoxy-benzamide) title compound from h / - (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-ylmethyl-5-trifluoromethoxy-benzamide (Compound H-1) under the same conditions as for Compound B- 3.
LCMS: m / z 562 [M + H] + HPLC retention time: 0.56 min (analysis condition A) [Example 297] Compound H-4 / V- (5-chloro-2-ethanesulfonyl-benzyl-3-r4- (tetrahydro-pyran-4-iD-piperazin-1-ylmethyl-5-trifluoromethoxy-benzamide) The title compound was synthesized from N- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-ylmethyl-5-trifluoromethoxy-benzamide (Compound H-1) under the same conditions as for the Compound B-4 LCMS: m / z 604 [M + H] H PLC retention time: 0.55 min (analysis condition A) [Example 298] Compound H-5 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -3- (4-ethyl-piperazin-1-ylmethyl) -5-trifluoromethoxy-benzamide Ethyl iodide (11 mL, 0.14 mmol) and potassium carbonate (48 mg, 0.35 mmol) were added to a solution of / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-ylmethyl. -5-trifluoromethoxy-benzamide (Compound H-1, 60 mg, 0.12 mmol) in DM F (1 ml) and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (MeOH / DCM) to yield the title compound (56.9 mg, 90%) as a substance colorless foam.
LCMS: m / z 548 [M + H] + H PLC retention time: 0.56 min (analysis condition A) [Example 299] Compound H-6 chloro-2-ethanesulfonyl-benzyl-3-piperazin-1-methylmethyl-5- trifluoromethyl-benzamide The title compound was synthesized from 3-bromo-5-trifluoromethyl-benzoic acid under the same conditions as for Compounds h 1, h 2, h 3, h 4 and H-1.
LCMS: m / z 504 [M + H] + HPLC retention time: 0.52 min (condition of Analysis A) [Example 300] Compound H-7 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -3- (4-methyl-piperazin-1-ylmethyl-5-trifluoromethyl-benzamide) The title compound was synthesized from N- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-methylmethyl-5-trifluoromethyl-benzamide (Compound H-6) under the same conditions as for the Compound B-2 LCMS: m / z 518 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 301] Compound H-8 A / - (5-chloro-2-ethanesulfonyl-benzyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -5-trifluoromethyl-benzamide The title compound was synthesized from N- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-ylmethyl-5-trifluoromethyl-benzamide (Compound H-6) under the same conditions as for the Compound B-3.
LCMS: m / z 546 [M + H] + H PLC retention time: 0.56 min (analysis condition A) [Example 302] Compound H-9 / V- (5-chloro-2-ethanesulfonyl-benzyl) -3-r4- (tetrahydro-pyran-4-yl) -piperazin-1-MmetiH-5-trifluoromethyl-benzamide The title compound was synthesized from N- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-ylmethyl-5-trifluoromethyl-benzamide (Compound H-6) under the same conditions as for the Compound B-4 LCMS: m / z 588 [M + H] + H PLC retention time: 1.52 min (analysis condition D) [Example 303] Compound h5 3-bromo-5-bromomethyl-benzoic acid The title compound was synthesized from 3-bromo-5-methyl-benzoic acid ethyl ester under the same conditions as for Compound b6.
[Example 304] Compound h6 7 ~ 4- (3-bromo-5-ethoxycarbonyl-benzyl) -pjperazine-1-carboxylic acid erc-butylester The title compound was synthesized from 3-bromo-5-bromomethyl-benzoic acid fer-t-butyl ester (Compound h5) and piperazine-1-carboxylic acid fer-butyl ester under the same conditions as for Compound g3.
[Example 305] Compound h7 4- (3-Bromo-5-carboxy-benzyl) -piperazine-1-carboxylic acid tert-butylester The title compound was synthesized from 4- (3-bromo-5-ethoxycarbonyl-benzyl) -piperazine-1-carboxylic acid fer-butyl ester (Compound h6) under the same conditions as for Compound g7.
[Example 306] Compound H-10 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-ylmethyl-benzamide The title compound was synthesized from 4- (3-bromo-5-carboxy-benzyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound h 7) under the same conditions as for Compounds h4 and H- 1 .
LCMS: m / z 514 [M + H] + HPLC retention time: 0.49 min (analysis condition A) [Example 307] Compound H-1 1 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl-5- (4-methyl-piperazin-1-ymethio-benzamide) The title compound was synthesized from 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-ylmethyl-benzamide (Compound H-10) under the same conditions as for the Compound B-2.
LCMS: m / z 528 [M + H] + HPLC retention time: 0.52 min (analysis condition A) [Example 308] Compound H-12 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5- (4-isopropyl-piperazin-1-methylmethyl) -benzamide The title compound was synthesized from 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-methylmethyl-benzamide (Compound H-10) under the same conditions as for Compound B-3.
LCMS: m / z 556 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 309] Compound H-13 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-r4- (tetrahydro-pyran-4-iP-piperazin-1-ylmethin-benzamide) The title compound was synthesized from 3-bromo-A / - (5- chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-methylmethyl-benzamide (Compound H-10) under the same conditions as for Compound B-4.
LCMS: m / z 598 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 310] Compound h8 3-chloro-5-methyl benzoic acid ethoster and synthesized the title compound from 3-chloro-5-methyl benzoic acid under the same conditions as for Compound b1.
[Example 31 1] Compound h9 Ethyl t-3-bromomethyl-5-chloro-benzoic acid The title compound was synthesized from 3-chloro-5-methyl-benzoic acid ethyl ester (Compound h8) under the same conditions as for Compound b6.
[Example 312] Compound h 10 4- (3-carboxy-5-chloro-benzyl) -piperazine-1 - butyl ester bli The title compound was synthesized from 3-bromomethyl-5-chloro-benzoic acid ethyl ester (Compound h 9) under the same conditions as for Compounds h6 and h7.
[Example 313] Compound H-14 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzin-5-piperazin-1-methylmethyl-benzamide) The title compound was synthesized from 4- (3-carboxy-5-chloro-benzyl) -piperazine-1-carboxylic acid te / c-butylester (Compound h10) under the same conditions as for Compounds h4 and H -1 .
LCMS: m / z 470 [M + H] + HPLC retention time: 1.25 min (analysis condition D) [Example 314] Compound H-15 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl-5- (4-methyl-piperazin-1 - Imethi-benzamide The title compound was synthesized from 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-methylmethyl-benzamide (Compound H-14) under the same conditions as for the Compound B-2.
LCMS: m / z 484 [M + H] HPLC retention time: 0.50 min (analysis condition A) [Example 315] Compound H-16 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5- (4-isopropyl-piperazin-1-ylmethyl-benzamide) The title compound was synthesized from 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-methylmethyl-benzamide (Compound H-14) under the same conditions as for the Compound B-3.
LCMS: m / z 512 [M + H] + H PLC retention time: 1.35 min (analysis condition D) [Example 316] Compound H-17 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzin-5-f4- (tetrahydro-pyran-4-yl) -piperazin-1-ylmethyl-benzamide The title compound was synthesized from 3-chloro-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-methylmethyl-benzamide (Compound H-14) under the same conditions as for the Compound B-4.
LCMS: m / z 554 [M + H] + H PLC retention time: 1.35 min (analysis condition D) [Example 317] Compound i1 3 5-dibromo benzoic acid ester The title compound was synthesized from 3,5-dibromo-benzoic acid under the same conditions as for Compound b1.
[Example 318] Compound i2 Tere- butyl ester of 4- (3-bromo-5-ethoxycarbonyl-phenyl) -piperazine-1-carboxylic acid A mixture of 3,5-dibromo-benzoic acid ethyl ester (Compound i 1, 1.5 g, 4.9 mmol), piperazine-1-carboxylic acid fer-t-butylester (907 mg, 4.9 mmol), cesium carbonate ( 4.76 g, 15 mmol), tris (dibenzylidene ketone) dipalladium (0) (504 mg, 0.49 mmol) and BI NAP (606 mg, 0.97 mmol) in toluene (25 ml) was stirred at 80 ° C overnight. The reaction solution was diluted with ethyl acetate, washed with saturated saline and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting residue after concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (1.05 g, 52%). ) as a pale yellow solid.
LCMS: m / z 413 [M + H] + H PLC retention time: 3.25 min (analysis condition C) [Example 319] Compound i3 Tere- butyl ester of 4- (3-bromo-5-carboxy-phenih-oiperazine-1-carboxylic acid The title compound was synthesized from 4- (3-bromo-5-ethoxycarbonyl-phenyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound 2) under the same conditions as for Compound g7.
[Example 320] Compound 4 4-R3-Bromo-5- (5-chloro-2-ethanesulfonyl-benzylcarbamom-phenyl-piperazine-1-carboxylic acid tert-butylester The title compound was synthesized from 4- (3-bromo-5-carboxy-phenyl) -piperazine-1-carboxylic acid-tert-butyl ester (Compound 3) under the same conditions as for Compound A-14.
[Example 321] Compound 1-1 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzin-5-p-piperazin-1-l-benzamide The title compound was synthesized from 4- [3-bromo-5- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -phenyl] -piperazine-1-carboxylic acid (4% Compound) under the same conditions as for Compound B-1.
LCMS: m / z 500 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 322] Compound I-2 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzin-5- (4-methyl-piperazin-1-yl) -benzamide The title compound was synthesized from 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-yl-benzamide (Compound 1-1) under the same conditions as for the Compound B-2.
LCMS: m / z 514 [M + H] + HPLC retention time: 0.51 min (analysis condition A) [Example 323] Compound I-3 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl-5- (4-isopropyl-piperazin-1 -? P-benzamide The title compound was synthesized from 3-bromo-A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-yl-benzamide (Compound 1-1) under the same conditions as for the Compound B-3. However, the reaction was performed by use of 1,4-dioxane instead of THF as a solvent and heating at 85 ° C.
LCMS: m / z 542 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 324] Compound I-4 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-r4- (tetrahydro-pyran-4-yl) -piperazin-1-in-benzamide The title compound was synthesized from 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-piperazin-1-yl-benzamide (Compound 1-1) under the same conditions as for the Compound B-4. However, the reaction was carried out using 1,4-dioxane instead of THF as solvent and heating at 85 ° C.
LCMS: m / z 584 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 325] Compound 1-5 / / - (5-Chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-yl-5-trifluoromethyl-benzamide The title compound was synthesized from 3-chloro-5-trifluoromethyl-benzoic acid under the same conditions as for Compounds i 1, 2, i 3, i4 and 1-1.
LCMS: m / z 490 [M + H] + HPLC retention time: 0.52 min (analysis condition A) [Example 326] Compound I-6 / N / - (5-chloro-2-ethanesulfonyl-benzyl) -3- (4-methyl-piperazin-1 -ih-5- t rif luoro metí l-be nza mida The title compound was synthesized from N- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-yl-5-trifluoromethyl-benzamide (Compound I-5) under the same conditions as for the Compound B-2 LCMS: m / z 504 [M + H] + H PLC retention time: 0.53 min (analysis condition A) [Example 327] Compound 1-7 A / - (5-Chloro-2-ethanesulfonyl-benzyl) -3- (4-isopropyl-p-eperazin-1-yl) -5-trifluoromethyl-benzamide title compound from N- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-yl-5-trifluoromethyl-benzamide (Compound I-5) under the same conditions as for Compound B-3 . However, the reaction was carried out using 1, 4-dioxane instead of TH F as solvent and heating at 85 ° C.
LCMS: m / z 532 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 328] Compound I-8 (5-chloro-2-ethanesulfonyl-benzyl) -3-r4- (tetrahydro-pyran-4-yl) - piperazin-1 - i -5-t rif I uorometi l-be nza mida The title compound was synthesized from N- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-yl-5-trifluoromethyl-benzamide (Compound I-5) under the same conditions as for the Compound B-4 However, the reaction was carried out using 1, 4-dioxane instead of THF as solvent and heating at 85 ° C.
LCMS: m / z 574 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 329] Compound 5 3-bromo-5-trifluoromethoxy-benzoic acid ester The title compound was synthesized from 3-bromo-5-trifluoromethoxy-benzoic acid under the same conditions as for Compound b1 [Example 330] Compound 6 Tere- butyl ester of 4- (3-ethoxycarbonyl-5-trifluoromethoxy-phen-0-pjperazine-1-carboxylic acid) The title compound was synthesized from 3-bromo-5-trifluoromethoxy-benzoic acid ethyl ester (Compound i5) under the same conditions as for Compound i2.
[Example 331] Composite 7 7 ~ 4- (3-carboxy-5-trifluoromethoxy-phenin-pe-1-carboxylic acid e-butylester The title compound was synthesized from 4- (3-ethoxycarbonyl-5-trifluoromethoxy-phenyl) -piperazine-1-fer-butyl ester. carboxylic (Compound i6) under the same conditions as for Compound b3.
[Example 332] Compound i8 Tere- butyl ester of 4-f3- (5-chloro-2-ethanesulfonylbenzylca rbamoiP-5-trifluoromethoxy-phen i1-piperazine-1-carboxylic acid The title compound was synthesized from 4- (3-carboxy-5-trifluoromethoxy-phenyl) -piperazine-1-carboxylic acid-tert-butylester (Compound i7) under the same conditions as for Compound A-14.
[Example 333] Compound I-9 A / - (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-yl-5-trifluoromethoxy-benzamide : The title compound was synthesized from urea-butyl ester 4- [3- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -5-trifluoromethoxy-phenyl] -piperazine-1-carboxylic acid (Compound 8) under the same conditions as for Compound B-1.
LCMS: m / z 506 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 334] Compound 1-10 / V- (5-chloro-2-ethanesulfonyl-benzyl) -3- (4-methyl-piperazin-1 -? P-5-trifluoromethoxy-benzamide) The title compound was synthesized from N- (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-yl-5-trifluoromethoxy-benzamide (Compound I-9) under the same conditions as for the Compound B-2 LCMS: m / z 520 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 335] Compound 1-1 1 AM5-chloro-2-ethanesulfonyl-benzyl) -3- (4-isopropyl-piperazin-1-in-5-trifluoromethoxy-benzamide The title compound was synthesized from h / - (5-chloro-2-ethanesulfonyl-benzyl) -3-piperazin-1-yl-5-trifluoromethoxy-benzamide (Compound I-9) under the same conditions as for Compound B-3.
LCMS: m / z 548 [M + H] + H PLC retention time: 0.56 min (analysis condition A) [Example 336] Compound 1-12 A / - (5-chloro-2-ethanesulfonyl-benzin-3-r4- (tetrahydro-pyran-4-in-pjperazin-1-in-5-trifluoromethoxy-benzamide) The title compound was synthesized from A / - (5-chloro-2- ethanesulfonyl-benzyl) -3-piperazin-1-yl-5-trifluoromethoxy-benzamide (Compound I-9) under the same conditions as for Compound B-4.
LCMS: m / z 590 [M + H] + HPLC retention time: 0.57 min (analysis condition A) [Example 337] Compound 9 3 - ((Sl-3-tert-butoxycarbonylamino-pyrrolidin-1 - ih 5 t ifl t xi-benzoic acid ester The title compound was synthesized from 3-bromo-5-trifluoromethoxy-benzoic acid ethyl ester (Compound i5) under the same conditions as for Compound I 2. However, the reaction was carried out using (S) -pyrrolidin-3-yl-carbamic acid fer-butylester in place of piperazine-1-carboxylic acid terebutylester.
[Example 338] Composite 10 3 - ((S) -3-tert-butoxycarbonylamino-pyrrolidin-1-iH-5-trifluoromethoxy-benzoic acid The title compound was synthesized from 3 - ((S) -3-tert-butoxycarbonylamino-pyrrolidin-1-yl) -5-trifluoromethoxy-benzoic acid ethyl ester (Compound 9) under the same conditions as for Compound g7.
[Example 339] Compound M 1 KS-tert-butylester) -1 -r3- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -5-trifluoromethoxy-phenyl-1-pyrrolidin-3-yl) -carbamic acid The title compound was synthesized from 3 - ((S) -3-tert-butoxycarbonylamino-pyrrolidin-1-yl) -5-trifluoromethoxy-benzoic acid (Compound i 10) under the same conditions as for Compound A- 14 [Example 340] Compound 1-13 3 - ((S) -3-amino-pyrrolidin-1-yl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -5- t rif lu gold methoxy-benze mida The title compound was synthesized from acid fer-butyl ester. { (S) -1 - [3- (5-Chloro-2-ethanesulfonyl-benzylcarbamoyl) -5-trifluoromethoxy-phenyl] -pyrrolidin-3-yl} -carbamic (Compound 1 1) under the same conditions as for Compound B-1.
LCMS: m / z 506 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 341] Compound 1-14 3 - ((S) -3-acetylamino-pyrrolidin-1 -iO- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoro-methoxy-benza mi da The title compound was synthesized from 3 - ((S) -3-amino-pyrrolidin-1-yl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -5- trifluoromethoxy-benzamide (Compound 1-13) under the same conditions as for Compound B-7.
LCMS: m / z 548 [M + H] + HPLC retention time: 0.77 min (analysis condition A) [Example 342] Compound 1-15 A / - (5-Chloro-2-ethanesulfonyl-benzyl) -3 - ((S) -3-methanesulfonylamino-pyrrolidin-1-yl-5-trifluoromethoxy-benzamide the title compound from 3 - ((S) -3-amino-pyrrolidin-1-yl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide (Compound 1-13 ) under the same conditions as for Compound B-9.
LCMS: m / z 584 [M + H] + HPLC retention time: 0.81 min (analysis condition A) [Example 343] Compound 1-16 3 - ((R) -3-Amino-pyrrolidin-1-yl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -5- trifluoromethoxy-benzamide ' The title compound was synthesized from 3-bromo-5-trifluoromethoxy-benzoic acid ethyl ester (Compound 5) under the same conditions as for Compounds i 9, i 10, 11 and 1-13. However, (R) -pyrrolidin-3-yl-carbamic acid fer-butylester was used in place of (S) -pyrrolidin-3-yl-carbamic acid-butylester under the conditions as for Compound 9.
LCMS: m / z 506 [M + H] HPLC retention time: 0.54 min (condition of analysis A) [Example 344] Compound 1-17 S-OFO-S-acetylamino-pyrrolidin-l-yl) -AM5-chloro-2-ethanesulfon ji be ncin-5-trifl uoromethoxy-benza mida The title compound was synthesized from 3 - ((R) -3- amino-pyrrolidin-1-yl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide (Compound 1-16) under the same conditions as for Compound B-7.
LCMS: m / z 548 [M + H] + HPLC retention time: 0.77 min (analysis condition A) [Example 345] Compound 1-18 / V- (5-Chloro-2-ethanesulfonyl-benzyl-3 - ((R) -3-methanesulfonylamino-i-lidi-1-P-5-t-romethoxy-benzamide The title compound was synthesized from 3 - ((R) -3-amino-pyrrolidin-1-yl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide (Compound 1 -16) under the same conditions as for Compound B-9.
LCMS: m / z 584 [M + H] + H PLC retention time: 0.81 min (analysis condition A) [Example 346] Compound 1-19 3- (4-amino-piperidin-1-m-AM5-chloro-2-ethanesulfonyl-benzin-5-trifluoromethoxy-benzamide .
The title compound was synthesized from 3-bromo-5-trifluoromethoxy-benzoic acid ethyl ester (Compound 5) under the same conditions as for Compounds i 9, 10, 11 and 1-13. However, piperidin-4-yl-carbamic acid-butylester in place of (S) -pyrrolidin-3-yl-carbamic acid fer-butylester under the conditions as for Compound i9.
LCMS: m / z 520 [M + H] HPLC retention time: 0.55 min (analysis condition A) [Example 347] Compound I-20 / VM5-chloro-2-ethanesulfonyl-benzyl-3- (4-dimethylamino-piperidin-1-ih-5-trifluoromethoxy-benzamide The title compound was synthesized from 3- (4-amino-piperidin-1-yl) -A / - (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide (Compound 1-19) under the same conditions as for Compound B-2. However, sodium triacetoxyborohydride was used in place of formic acid and 1,2-dichloroethane was used as the solvent.
LCMS: m / z 548 [M + H] + HPLC retention time: 0.56 min (analysis condition A) [Example 348] Compound 1-21 3- (4-Acetylamino-piperidin-1-yl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide The title compound was synthesized from 3- (4-amino-piperidin-1-yl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide (Compound 1-19) under the same conditions as for Compound B-7.
LCMS: m / z 562 [M + H] + H PLC retention time: 0.76 min (analysis condition A) [Example 349] Compound I-22 / V- (5-chloro-2-ethanesulfonyl-benzyl) -3- (4-methanesulfonylamino-piperidin-1 -i h-5-triflu or romethoxy-benzam id a The title compound was synthesized from 3- (4-amino-piperidin-1-yl) - / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide (Compound 1-19 ) under the same conditions as for Compound B-9.
LCMS: m / z 598 [M + H] + H PLC retention time: 0.80 min (analysis condition A) [Example 350] Compound I-23 / V- (5-chloro-2-ethansulfonyl-benzyl) -3- (3,3-dimethyl-piperazin-1-yl) -5-trifluoromethoxy-benzamide The title compound was synthesized from 3-bromo-5-trifluoromethoxy-benzoic acid ethyl ester (Compound i 5) under the same conditions as for Compounds i 9, i 10, i 1 1 and 1-13. However, 2,2-dimethyl-piperazine-1-carboxylic acid fer-butyl ester was used in place of (S) -pyrrolidin-3-yl-carbamic acid terebutyl ester under the conditions as for Compound 9.
LCMS: m / z 534 [M + H] + HPLC retention time: 0.57 min (analysis condition A) [Example 351] Compound I-24 / V- (5-Chloro-2-ethanesulfonyl-benzyl) -3- (4-hydroxy-piperidin-1-yl) -5- t-triflu-oro-methoxy-benza-mida The title compound from 3-bromo-5-trifluoromethoxy-benzoic acid ethyl ester (Compound i5) under the same conditions as for Compounds i 9, i 10 and i 1 1. However, the reaction was carried out using 4-hydroxy-piperidine in place of (S) -pyrrolidin-3-yl-carbamic acid fer-butylester under the conditions as for Compound i 9; using a solution 1 N sodium hydroxide aqueous in place of an aqueous solution of 6N sodium hydroxide under the conditions as for Compound i 10; and using DCM instead of DMF as a solvent under the conditions as for Compound i 1 1.
LCMS: m / z 521 [M + H] + HPLC retention time: 0.78 min (analysis condition A) [Examples 352 to 355] The following compounds of Table 10 were synthesized using 3-bromo- / V- (5-chloro-2-ethanesulfonyl-benzyl) -5-trifluoromethoxy-benzamide (Compound A-10) and corresponding cyclic amines under the same conditions as for Compound 2 [Table 10] [Example 356 Compound j 1 Ethyl ester of 4-bromo-3-trifluoromethylbenzoic acid The title compound was synthesized from 4-bromo-3-trifluoromethylbenzoic acid under the same conditions as for Compound b1.
[Example 357] Compound j2 Tere- butyl ester of 4- (4-ethoxycarbonyl-2-trifluoromethyl-phenihp ppe a nd 1 -carboxylic acid The title compound was synthesized from 4-bromo-3-trifluoromethylbenzoic acid ethyl ester (Compound j1) under the same conditions as for Compound i2.
[Example 358] Compound j3 4- (4-carboxy-2-trifluoromethyl-phenyl-1-bicyclic acid tert -butylester The title compound was synthesized from 4- (4-ethoxycarbonyl-2-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid-tert-butylester (Compound j 2) under the same conditions as for Compound g7.
[Example 359] Compound j4 Tere-butyl ester of 4-G4- (5-chloro-2-ethane its sulphonic acid) -2-triflu or rom ethyl-ethyl or P-pi pe razi-1-carboxylic acid The title compound was synthesized from 4- (4-carboxy-2-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid-tert-butylester (Compound j3) under the same conditions as for Compound A-14.
[Example 360] Compound J-1 / V- (5-chloro-2-ethanesulfonyl-benzin-4-piperazin-1-yl-3-trifluoromethyl-benzamide) The title compound was synthesized from 4- [4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -2-trifluoromethyl-phenyl] -piperazine-1-carboxylic acid-tert-butylester (Compound j4) under the same conditions as for Compound B-1.
LCMS: m / z 490 [M + H] + H PLC retention time: 1.42 min (condition of D analysis) [Example 361] Compound j5 7 ~ 4- (4-Ethoxycarbonyl-2-trifluoromethoxy-phenyl) -piperazine-1-carboxylic acid er-butyl ester The title compound was synthesized from 4-chloro-3-trifluoromethoxy-benzoic acid ethyl ester under the same conditions as for Compound I 2.
[Example 362] Compound j6 Tere-butyl ester _ of _ acid _ 4- (2-chloro-4-ethoxycarbonyl-6-trifluoromethoxy-phenih-piperazine-l -carboxylic acid The title compound was synthesized from 4- (4-ethoxycarbonyl-2-trifluoromethoxy-phenyl) -piperazine-1-carboxylic acid fer-t-butyl ester (Compound j5) under the same conditions as for Compound d2.
[Example 363] Composite 7 4- (4-carboxy-2-chloro-6-trifluoromethoxy) butyl ester P-piperaz i na-1-carboxylic acid The title compound was synthesized from 4- (2-chloro-4-ethoxycarbonyl-6-trifluoromethoxy-phenyl) -piperazine-1-carboxylic acid fer-t-butylester (Compound j6) under the same conditions as for Compound b3 .
[Example 364] Compound j8 Tere- butylester of 4-r2-chloro-4- (5-chloro-2-ethanesulfonyl-benzyl) rbamoy-6-trifluoromethoxy-phen-P-pi pe ra ny a-1-carboxylic acid The title compound was synthesized from 4- (4-carboxy-2-chloro-6-trifluoromethoxy-phenyl) -piperazine-1-carboxylic acid terebutyl ester (Compound j 7) under the same conditions as for Compound A-14.
[Example 365] Compound J-2 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl-4-oo-erazin-1-yl-5-trifluoromethoxy-benzamide) The title compound was synthesized from 4- [2-chloro-4- (5-chloro-2-ethanesulfonyl-benzylcarbamoyl) -6-trifluoromethoxy-phenyl] -piperazine-1-carboxylic acid fer-butyl ester (Compound j8 ) under the same conditions as for Compound B-1.
LCMS: m / z 540 [M + H] + H PLC retention time: 0.54 min (analysis condition A) [Example 366] Compound J-3 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl-4- (4-methyl-piperazin-1-yl) - 5-trifluoromethoxy-benzamide The title compound was synthesized from 3-chloro- / V- (5-chloro-2-ethanesulfonyl-benzyl) -4-piperazin-1-yl-5-trifluoromethoxy-benzamide (Compound J-2) under the same conditions like for Compound B-2.
LCMS: m / z 554 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 367] Compound bb1 4-f (3-amnofenihmetin-3- (ethyl trifluoromethylbenzoate A suspension of ethyl 4- (bromomethyl) -3- (trifluoromethyl) benzoate (Compound b6, 30.0 mg, 0.096 mmol), (3-aminophenyl) boronic acid (18.5 mg, 0.135 mmol), potassium carbonate (40.0 mg, 0.289 mmol) and tetrakis (triphenylphosphine) palladium (0) (11.1 mg, 9.64 pmol) in a mixed solvent of 1,2-dimethoxyethane / water (2/1) (0.9 ml) was stirred at 70 ° C for two hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with brine and then dried over drous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (20.0 mg, 64%) as a yellow oily substance.
LCMS: m / z 324 [M + H] + HPLC retention time: 0.80 min (condition of F analysis) [Example 368] Compound bb2 4 - [(3-aminophenyl) methyl1-3- (trifluoromethyl) benzoic acid Synthesis of the title compound was performed from ethyl 4 - [(3-aminophenyl) methyl] -3- (trifluoromethyl) benzoate (Compound bb1) under the same conditions as for Compound b8.
[Example 369] Compound BB-1 4-r (3-aminophenyl) methyH-N-f (5-chloro-2-ethylsulfonylphenimethyl-3- (trifluoromethylbenzamide Synthesis of the title compound was carried out from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound A-21.
However, 4 - [(3-aminophenyl) methyl] -3- (trifluoromethyl) benzoic acid (Compound bb2) was used in place of 3- (trifluoromethyl) benzoic acid.
LCMS: m / z 51 1 [M + H] + HPLC retention time: 0.76 min (condition of F analysis) [Example 370] Compound BB-2 N-f (5-chloro-2-ethylsulfonylphenin methyl n-4- (pyridin-4-yl methyl P -3- (trifluoromethyl) benzamide Synthesis of the title compound was carried out from ethyl 4- (bromomethyl) -3- (trifluoromethyl) benzoate (Compound b6) under the same conditions as for bb1, bb2 and BB-1. However, 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-i) pyridin was used instead of (3-aminophenii) boronic acid under the conditions for the Compound bb1, and 4- (pi-rid-4-ylmethyl) -3- (trifluoromethyl) benzoic acid was used in place of 4 - [(3-aminophenyl) methyl] -3- (trifluoromethyl) benzoic acid (Compound bb2) the conditions for Compound BB-1.
LCMS: m / z 497 [M + H] + H PLC retention time: 0.57 min (F analysis condition) [Example 371] Compound bb3 4-f [4-ethoxycarbonyl-2- -3-dihydro-2H-pyridine-1-ferro-butylcarboxylate Synthesis of the title compound was carried out from ethyl 4- (bromomethyl) -3- (trifluoromethyl) benzoate (Compound b6) under the same conditions as for Compound bb1. However, 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-fer-butylcarboxylate was used instead of (3-aminophenyl) boronic acid.
[Example 372] Compound bb4 4-rf4-Ethoxycarbonyl-2- (trifluoromethylphenolmethotine-1-carboxylic acid tere-butyl ester 10% Palladium activated carbon (10 mg) was added to a solution of ferric 4 - [[4-ethoxycarbonyl-2- (trifluoromethyl) phenyl] methyl] -3,6-dihydro-2H-pyridine-1-carboxylate. -butyl (Compound bb3, 34.0 mg, 82.2 pmol) in MeOH (1 mL), and the mixture was stirred at room temperature for 16 hours under an atmosphere of hydrogen. DCM was added to the reaction mixture; and then the mixture was filtered through a membrane filter, the title compound (31.0 mg, 91%) as a colorless oily substance concentrating the filtrate under reduced pressure.
LCMS: m / z 416 [M + H] + H PLC retention time: 1.10 min (analysis condition F) [Example 373] Compound bb5 4-fM -f (2-methylpropan-2-yl) oxycarboninpiperidin-4-ylmethyl-3- (trifluoromethyl) benzoic acid Synthesis of the title compound was carried out from ferrubutyl 4- [[4-ethoxycarbonyl-2- (trifluoromethyl) phenyl] methyl] piperidine-1-carboxylate (Compound bb4) under the same conditions as for Compound b8 .
[Example 374] Compound bb6 4-rf4-f (5-Chloro-2-ethylsulfonyl-phenylmethylcarbamom-2- (trifluoromethyl) phenyl-1-piperidine-1-ferro-butylcarboxylate The synthesis of the title compound was performed from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound A-21. However, 4 - [[1 - [(2-methylpropan-2-yl) oxycarbonyl] piperidin-4-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound bb5) was used instead of 3- ( trifluoromethyl) benzoic acid. [Example 375] Compound BB-3 N-f (5-chloro-2-ethylsulfonylphenol) methyl-4- (piperidin-4-ylmethyl) -3- (trifluoromethylbenzamide) Synthesis of the title compound was performed from 4- [[4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -2- (trifluoromethyl) phenyl] methyl] piperidine-1-ferrobutylcarboxylate (Compound bb6) under the same conditions as for Compound B-1.
LCMS: m / z 503 [M + H] + HPLC retention time: 0.54 min (condition of F analysis) [Example 376] Compound BB-4 N-r (5-Chloro-2-ethylsulfonyl) -lfyninmethyl-4-f (1-methylpiperidin-4-immethyl-3- (trifluoromethyl) benzamide is s of the title compound from N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperidin-4-ylmethyl) -3- (trifluoromethyl) benzamide (Compound BB-3) under the same conditions as for Compound B-2.
LCMS: m / z 517 [M + H] + H PLC retention time: 0.54 min (analysis condition F) [Example 377] Compound bb7 1.5-d icloro-2-eta nsu Ifon i l-3-meti I-benzene 2,4-Dichloro-6-methyl-benzenesulfonyl chloride (1.00 g, 3.90 mmol) was added to an aqueous solution (5 mL) of sodium sulfite (534 mg, 4.24 mmol) and sodium bicarbonate (712 mg, 8.48 mmol), and the mixture was stirred at 75 ° C for one hour. Iodoethane (1.98 ml, 19.0 mmol) was added thereto, and the mixture was stirred at 100 ° C for 11 hours. Iodoethane (0.988 mL, 9.60 mmol) was added, and the mixture was stirred at 100 ° C for three more hours. HE extracted the reaction solution by adding DCM; and the organic layer was washed with a saturated aqueous solution of sodium thiosulfate and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (664 mg, 68%) as a colorless oily substance.
LCMS: m / z 253 [M + H] + H PLC retention time: 0.79 min (analysis condition D) [Example 378] Compound bb8 1 - . 1 - (bromomethyl) -3,5-dichloro-2-ethylsulfonyl benzene Synthesis of the title compound was carried out from 1,5-dichloro-2-ethanesulfonyl-3-methyl-benzene (Compound bb7) under the same conditions as for Compound b6. However, acetonitrile was used in place of carbon tetrachloride as the solvent.
[Example 379] Compound bb9 (3,5-dichloro-2-ethylsulfonylphenyl) methanamine An aqueous 25% ammonium solution (4 mL) was added to a solution of 1- (bromomethyl) -3,5-dichloro-2-ethylsulfonylbenzene (Compound bb8, 140 mg, 0.422 mmol) in EtOH (2 mL) under cooling with ice, and the mixture was warmed to room temperature and stirred for 30 minutes. In addition, THF (2 mL) was added to the reaction suspension, and the reaction solution was stirred at room temperature for two hours. Then, the reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane). The resulting mixture was further purified by silica gel column chromatography (ethyl acetate / n-hexane, then methanol / dichloromethane) to yield the title compound (81.9 mg, 72%) as a yellow oily substance pale.
LCMS: m / z 268 [M + H] + HPLC retention time: 0.36 min (analysis condition A) [Example 380] Compound bb10 4- (3,5-Dichloro-2-ethylsulfonylphenyl) methylcarbamoyl-2- (trifluoromethylphenylmethylpiperazine-1-carboxylic acid t-butyl ester DIPEA (18.0 ml, 0.101 mmol) was added to a solution of (3,5-dichloro-2-ethylsulfonylphenyl) methanamine (Compound bb9, 12.3 mg, 45.8 pmol), 4 - [[4 - [(2-methylpropan-2 -yl) oxycarbonyl] piperazin-1-yl] methyl] -3- (trifluoromethyl) benzoate (Compound b3, 20.1 mg, 47.1 pmol) and HATU (21.4 mg, 56.3 pmol) in DMF (0.5 ml), and The mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (20.2 mg, 69%) as a colorless foamy substance.
LCMS: m / z 638 [M + H] + HPLC retention time: 1.84 min (analysis condition D) [Example 381] Compound bb1 1 N-α (3,5-dichloro-2-ethylsulfonylphenyl) metill-4- (p-piperazin-1-methylmethi-3- (t rif luorometi libe nza mide Synthesis of the title compound was performed from 4- [[4 - [(3,5-dichloro-2-ethylsulfonylphenyl) methylcarbamoyl] -2- (trifluoromethyl) phenyl] methyl] piperazine-1-ferrobutylcarboxylate (Compound bb10) under the same conditions as for Compound B-57.
[Example 382] Compound BB-5 N-f (3,5-dichloro-2-ethylsulfonylphenyl) methyl-4-r (4-methylpiperazin-1-yl) metin-3- (trifluoromethyl) benzamide of the title compound from IM- [(3,5-dichloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-ylmethyl) -3- (trifluoromethyl) benzamide (Compound bb1 1) under the Same conditions as for Compound B-2.
LCMS: m / z 552 [M + H] + HPLC retention time: 1.53 min (condition of D analysis) [Example 383] Compound BB-6 N-f (3,5-dichloro-2-ethylsulfonylphenyl) metin-4- 3- (methylamino) piperidin-1 -Hmetin-3- (trifluorom e t i I) b in z a m i d a is the title compound from (3,5-dichloro-2-ethylsulfonylphenyl) methanamine (Compound bb9) under the same conditions as for Compounds bb10 and bb1 1. However, 4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -3- (trifluoromethyl) benzoate (Compound b17) was used. ) instead of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- (trifluoromethyl) benzoate (Compound b3) under the conditions for Compound bb10.
LCMS: m / z 566 [M + H] + HPLC retention time: 1.33 min (analysis condition D) [Example 384] Compound DD-1 N-r (3S) -1-phenyl-2-chloro-4-yl-5-chloro-2-ethylsulfonyl-phenylmethylcarbamoyl-6- (trifluoromethyl) -phenymethylpiperidin-3-iH-1 H-pyrrole-2-carboxamide A solution of 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound D -18, 30.0 mg, 0.054 mmol), pyrrole-2-carboxylic acid (7.24 mg, 0.065 mmol) and DIPEA (27.0 mL, 0.163 mmol) in DCM (1 mL) was cooled to 0 ° C in an ice water bath , HBTU (24.7 mg, 0.065 mmol) was added, and the mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was then purified by preparative H PLC (water / acetonitrile, 0.05% TFA) to yield the title compound (22.0 mg, yield: 62%) as a colorless solid. .
LCMS: m / z 645 [M + H] + H PLC retention time: 0.64 min (analysis condition F) [Examples 385 to 387, Examples 402 to 404] The compounds of Table 11 below were synthesized using 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] - 5- (trifluoromethyl) benzamide (Compound D-18) and the corresponding carboxylic acids under the same conditions as for Compound DD-1.
[Table 1 1] [Example 388] Compound dd1 chloro-4-y (5-chloro-2- Ethyl-sulfonyl-phenylmethylcarbamoyl-6- (trifluoromethyl-phenylmethylpiperidine-3-incarbamompyrrolidine-1-tert-butyl carboxylate) Synthesis of the title compound was carried out from 4- [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] - 5- (trifluoromethyl) benzam ida (Compound D-18) under the same conditions as for Compound DD-1. However, as a carboxylic acid, (2S) -1 - [(2-methylpropan-2-yl) oxycarbonyl] pyrrolidine-2-carboxylic acid was used in place of 1 H-pyrrole-2-carboxylic acid.
[Example 389] Compound DD-5 (2S) -N-f (3S) -1 -rr2-chloro-4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamom-6- (trifluoromethyl) phenylHmetinpiperidin-3-inpyrrolidine-2-carboxamide Synthesis of the title compound was performed from (2S) -2 - [[(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin-3-yl] carbamoyl] pyrrolidine-1-fer-butylcarboxylate (Compound dd 1) under the same conditions as for Compound B-1.
LCMS: m / z 649 [M + H] + HPLC retention time: 0.48 min (condition of F analysis) [Examples 390 to 401] The compounds of Table 12 below were synthesized using 4 - [[(3S) -3-aminopiperidin-1 -yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benzamide (Compound D-18) and corresponding carboxylic acids under the same conditions as for Compounds dd 1 and DD-5.
[Table 12] [Example 405] Compound DD-21 3-chloro-Nr (5-chloro-2-ethylsulfonylphenyl) methyll-4-rf (3S) -3- (propan-2-alamide) pi pe rid i n- 1 -inmetin-5 - (trifluoromethyl benzamide Synthesis of the title compound was carried out from 4- [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benzamide (Compound D-18) under the same conditions as for Compound B-3. However, methanol was used in place of THF as the solvent.
LCMS: m / z 594 [M + H] H PLC retention time: 0.59 min (analysis condition F) [Example 406] 3-Bromopropin (16.0 ml, 0.181 mmol) was added to a solution of 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) ) methyl] -5- (trifluoromethyl) benzamide (Compound D-18, 50.0 mg, 0.091 mmol) and DIPEA (47.0 ml, 0.272 mmol) in chloroform (1 ml), and the mixture was then stirred at room temperature for 16 hours . The reaction mixture was concentrated under reduced pressure, and the resulting residue was then purified by preparative HPLC (water / acetonitrile, 0.05% TFA) to yield Compound DD-22 (17.5 mg, 32%) and Compound DD-23 (7.1 mg, 12%) independently as yellow solids.
Compound DD-22 3-chloro-N- f (5-chloro-2- -4-rr (3S) -3- (prop-2-ynylamino) piperidin-1-inmetill-5- (trifluoromethyl) benzamide LCMS: m / z 590 [M + H] + HPLC retention time: 0.59 min (condition of F analysis) Compound DD-23 4-ff (3S) -3-fbis (prop-2-inihaminolpiperidin-1-methylmethyl-3-chloro-N-r (5-chloro-2-ethylsulfonylphenimidemethyl-5- (trifluoromethylbenzamide p HPLC: 0.67 min (condition of analysis F) [Example 407] Compound DD-24 3-chloro-N-f (5-chloro-2- -3- (cyanomethylamino) piperidin-l-inmetin-5- (trifluoromethyl) benzamide Synthesis of the title compound was carried out from 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benzamide (Compound D-18) under the same conditions as for Compounds DD-22 and DD-23. However, 2-iodoacetonitrile was used instead of 3-bromopropin.
LCMS: m / z 591 [M + H] + HPLC retention time: 0.55 min (F analysis condition) [Example 408] Compounds DD-25 and DD-26 were synthesized from 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound D-18) under the same conditions as for Composites DD-22 and DD-23. However, bromoacetamide was used in place of 3-bromopropin.
} Compound DD-25 4-rf (3S) -3-r (2-amino-2-oxoethyl) aminolDiDeridin-1 -illmetin-3-chloro- N - [(5-chloro-2-ethylsulfonylphenyl) methyl-5- (trifluoromethyl) benzamide LCMS: m / z 609 [M + H] HPLC retention time: 0.56 min (condition of F analysis) Compound DD-26 4-ff (3S) -3-bis (2-amino-2-oxoetinaminolpiperidin-1-methylmethyl-3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) metin-5- (trifluoromethyl) benzamide LCMS: m / z 666 [M + H] + HPLC retention time: 0.47 min (condition of F analysis) [Example 409] Compound dd2 N-chloro-4-r (5-chloro-2- Ethyl sulfonylphenyl) methylcarbamoyH-6- (trifluoromethylphenillmetinpperidin-3-inaminoleti-tere-butylcarbamate) Synthesis of the title compound was carried out from 4- [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benzamide (Compound D-18) under the same conditions as for Compound H-5. However, urea-butyl (2-bromoethyl) carbamate was used in place of iodoethane.
[Example 410] Compound DD-27 4-r [(3S) -3- (2-aminoethylamino) piperidin-1-y-N-methyl-3-chloro-N-f (5-chloro-2-ethylsulfonyl-phenyl) -methyl-5- (trifluoromethylbenzamide Synthesis of the title compound was carried out from N [2 - [[(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] ] methyl butyl] piperidin-3-yl] amino] ethyl] carbamate (Compound dd2) under the same conditions as for Compound B-1.
LCMS: m / z 595 [M + H] + HPLC retention time: 0.45 min (condition of F analysis [Example 41 1] Compound DD-28 3-chloro-N-r (5-chloro-2-ethylsulfonylpheniPmetiH-4-rr (3S) -3- (oxetan-3-ylamino) piperidin-1 -illmetin-5- (trifluoromethylbenzamide Sodium triacetoxyborohydride (20 mg, 0.095 mmol) was added to a suspension of 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5-chloro-2-ethylsulfonyl) !) methyl] -5- (trifluoromethyl) benzamide (Compound D-18, 35 mg, 0.063 mmol) and 3-oxetanone (6 mL, 0.095 mmol) in chloroform (1 mL); and the mixture was stirred at room temperature. After 20 hours, 3-oxetanone (6 ml, 0.095 mmol) and sodium triacetoxyborohydride (25 mg, 0.1 18 mmol) were added further; and the mixture was further stirred at room temperature for four hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was then concentrated under reduced pressure. The resulting residue was purified by preparative H PLC (water / acetonitrile, 0.05% TFA) to yield the title compound (19 mg, 49%) as a solid. colorless.
LCMS: m / z 608 [M + H] + HPLC retention time: 0.56 min (condition of F analysis) [Example 412] Compound DD-29 3-chloro-N-r (5-chloro-2-ethylsulfonylphen-Pne-4-rr (3S) -3- (2,2-difluoroethylamino) piperidin-1-trimethoxy-5- (trifluoromethylbenzamide 2,2-Difluoroethyl trifluoromethanesulfonate (25.6 mg, 0.119 mmol) was added to a solution of 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-N - [(5- chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound D-18, 55.0 mg, 0.100 mmol) and DI PEA (21 .0 ml, 0.1 19 mmol) in THF (1 ml), and stirred at 70 ° C for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (51.0 mg, 83%) as a colorless solid.
LC S: m / z 616 [M + H] + H PLC retention time: 0.59 min (analysis condition F) [Example 413] 5 Compound dd3 N-r2-rr (3S) -1-r²-chloro-4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-6- (trifluoromethyl) phenyl-methylpiperidin-3-yl-methylaminol-tere-butyl-2-oxoetylcarbamate to Synthesis of the title compound was carried out from 3-chloro-N- (5-chloro-2-ethanesulfonyl-benzyl) -4 - ((S) -3-methylamino-piperidin-1-methylmethyl) -5-trifluoromethyl -benzamide (Compound D-26) under the same conditions as for Compound DD-1. However, 2 - [(2-methylpropan-2-yl) oxycarbonylamino] acetic acid was used in place of 1 H-pyrrol-2-carboxylic acid as a carboxylic acid.
[Example 414] Compound DD-30 25 4-ff (3S) -3 - [(2-aminoacetin-methylaminolpiperidin-1-methylmethyl-3-chloro- N-r (5-Chloro-2-ethylsulfonyl-N-NM-N- (trifluoromethylbenzamide Synthesis of the title compound was carried out from fer-butyl N- [2 - [[(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- ( trifluoromethyl) phenyl] methyl] pipendin-3-yl] -methylamino] -2-oxoethyl] carbamate of (Compound dd3) under the same conditions as for Compound B-57.
LCMS: m / z 623 [M + H] + HPLC retention time: 0.45 min (condition of F analysis) [Example 415] Compound dd4 4-amino-3-chloro-5- (trifluoromethylbenzoic acid Synthesis of the title compound was carried out from 4-amino-3- (trifluoromethyl) benzoic acid under the same conditions as for Compound d6.
[Example 416] Compound dd5 Methyl 4-amino-3-chloro-5- (trifluoromethyl) benzoate l g g sulfuric acid (48 ml) to a solution of 4-amino-3-chloro-5- (trifluoromethyl) benzoic acid (Compound dd4, 216 g, 901 mmol) in MeOH (1.08 I) at room temperature, and stirred under reflux for 13 hours. The reaction mixture was cooled to room temperature, and the pH was then adjusted to 9 by adding an aqueous solution (2.59 I) of tripotassium phosphate (191 g, 901 mmol). The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to yield the title compound (216 g, 95%) as a pale orange solid. 1 H NMR (400 MH DMSO d) 6 7 99 (1 H d J = 2.0 Hz), Sulfuric acid (91 ml) was added to a solution (1.73 I) of methyl 4-amino-3-chloro-5- (trifluoromethyl) benzoate (Compound dd5, 216 g, 853 mmol) in trifluoroethanol at room temperature, and cooled to -5 ° C, after which an aqueous solution (324 ml) of sodium nitrite (64.7 g, 938 mmol) was added over 24 minutes, and stirred for 30 minutes. An aqueous solution (324 ml) of potassium iodide (149 g, 895 mmol) was added at the same temperature for 30 minutes, and stirred at 0 ° C for 90 minutes, after which an aqueous solution was added ( 2.16 L) of sodium thiosulfate (215 g, 1.71 mol) for 25 minutes. The reaction mixture was warmed to 20 ° C; and the precipitate was collected by filtration, washed a mixed solution of ethanol / water (1: 1, 2.16 I), and then dried under reduced pressure to yield the title compound (205 g, 66%) as a solid. pale brown. 1 H-RM N (400 MHz, DMSO-d6) d: 8.26 (1 H, d, J = 1.8 Hz), 8.03 (1 H, d, J = 1.8 Hz), 3.90 (3 H, s) ). 15 [Example 418] Compound dd7 Methyl 3-chloro-4- (hydroxymethyl) -5- (trifluoromethyl) benzoate A solution of methyl 3-chloro-4-iodo-5- (trifluoromethyl) benzoate (Compound dd6, 500 mg, 1.37 mmol) in THF (2.7 ml) was cooled to 0 ° C in an ice water bath, a solution of isopropylmagnesium bromide / THF 0.74 M (2.23 ml, 1.65 mm) was added 25 mmol) dropwise, and stirred at the same temperature for 20 minutes. minutes Then N-formylmorpholine (0.277 mL, 2.74 mmol) was added, stirred at room temperature for two hours. The reaction mixture was again cooled to 0 ° C in an ice water bath, sodium borohydride (78.0 mg, 2.06 mmol) was added, and stirred at the same temperature for 20 minutes. Then, sodium borohydride (40.0 mg, 1.06 mmol) was further added, and stirred at the same temperature for 10 minutes. A solution of 1 N hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (223 mg, 60%) as an orange oily substance.
LCMS: m / z 269 [M + H] HPLC retention time: 0.68 min (F analysis condition) [Example 419] Compound dd8 3-Chloro-4- (hydroxymethyl) -5- (trifluoromethylbenzoic acid Synthesis of the title compound was carried out from methyl 3-chloro-4- (hydroxymethyl) -5- (trifluoromethyl) benzoate (Compound dd7) under the same conditions as for Compound b8. However, methanol was used in place of ethanol 5 as solvent.
[Example 420] Compound dd9 3-chloro-N-r (5-chloro-2-ethylsulfonylphennin-4-hydroxymethin-5- (trifluoromethyl) benzamide) The synthesis of the title compound was performed from 5-Chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compound A-21. However, 3-chloro-4- (hydroxymethyl) -5- (trifluoromethyl) benzoic acid (Compound d d 8) was used in place of 3- (trifluoromethyl) benzoic acid as a carboxylic acid. 20 [Example 421] Compound dd10 f2-chloro-4-f (5-chloro-2-ethylsulfonylphenimethylcarbamom-6- (trifluoromethylphenillmethyl meta nsulfon ato Methanesulfonyl chloride (0.082 ml, 1.06 mmol) was added to a solution of 3-chloro-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (hydroxymethyl) -5- (trifluoromethyl) benzamide ( Compound dd9, 383 mg, 0.814 mmol) and triethylamine (0.340 mL, 2.44 mmol) in DCM (4 mL) while cooling to 0 ° C in an ice water bath, and stirred at the same temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (305 mg, 68%) as a colorless solid.
LCMS: m / z 548 [M + H] + H PLC retention time: 0.80 min (analysis condition F) [Example 422] Compound dd1 1 N-f chloro-4-f (5-chloro-2-ethylsulfonylphenimmethylcarbamom-6-) (Trifluoromethyl) phenylmethylpiperidine-3-in-N-ethylcarbamate tert-butyl Tert-butyl / V-ethyl- / V - [(3S) -pyridin-3-yl] carbamate (37.5 mg, 0.164 mmol) was added to a methanesulfonate solution of [2-chloro-4 - [( 5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl (Compound dd10, 30.0 mg, 0.055 mmol) in DMF (0.5 ml), and stirred at 50 ° C for one hour. Ferric-butyl A / -ethyl- / V - [(3S) -piperidin-3-yl] carbamate (6.0 mg, 0.0263 mmol) was further added to the reaction mixture, and stirred at the same temperature for one hour . Then, urea-butyl V-ethyl- / [- (3S) -piperidin-3-yl] carbamate (6.0 mg, 0.0263 mmol) was further added, and stirred at the same temperature for one hour. The reaction mixture was cooled to room temperature and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (39.0 mg, quant.) As a colorless solid.
LCMS: m / z 680 [M + H] + HPLC retention time: 0.83 min (condition of F analysis) [Example 423] Compound DD-31 3-chloro- / V-r (5-chloro-2-ethylsulfonyl-phenylethyt-4-rf (3S) -3- (ethylaminol-Di-Dididin-1 -n-ethyl-5- (trifluoromethylbenzamide Synthesis of the title compound was carried out from N - [(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperdin-3-yl] - / tert-butyl V-ethyl carbamate (Compound dd 1 1) under the same conditions as for Compound B-1.
LCMS: m / z 580 [M + H] H PLC retention time: 0.58 min (analysis condition F) [Example 424] Compound DD-32 3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (3,6-diazabicyclo [3.1.1] heptan-3-methylmethyl) -5- (trifluoromethyl) benzamide Synthesis of the title compound was carried out from [2-chloro-4 - [(5-chloro-2-ethanesulfonate ethylsulfonMethyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl (Compound dd10) under the same conditions as for Compounds d d 1 1 and DD-31. However, the reaction was performed by using 3,6-diazabicyclo [3.1. 1] heptane-6-carboxylic acid butylcarbonate in place of / V-et i I -A / - [(3S) -pi perid i n-3- i. The ferd-butyl ester was added and triethylamine was added under the conditions for Compound dd 1 1.
LCMS: m / z 550 [M + H] + H PLC retention time: 0.55 min (F analysis condition) ío [Example 425] Compound DD-33 N-r (3S) -1-rr2-chloro-4-r (5-chloro-2-ethylsulfonylpheni0methylcarbamoan-6- (trifluoromethylpheniHmetinpiperidin-3-y-pyridine-2-carboxamide The synthesis of the title compound was carried out from [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl methanesulfonate (Compound dd10) under the same conditions as for Compound dd 11. However, the reaction was performed using A / - [(3S) -pi perid i h-3-i I] pyridine-2-carboxamide dihydrochloride instead of A / - ethyl-A / - [(3S) -piperidi h-3-yl] carbam-tert-butyl ester and potassium carbonate was added.
LCMS 25: m / z 657 [M + H] + HPLC retention time: 0.76 min (condition of F analysis) [Examples 426, 432 and 436 to 437] The compounds of Table 13 below were synthesized using [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl methanesulfonate (Compound dd 10) and corresponding amines under the same conditions as for Compounds dd1 1 and DD-31.
[Table 13] [Example 427] Compound dd12 / V-rf (2R) -1 -ff2-chloro-4-r (5-chloro-2-ethylsulfonylphenimethylcarbamom-6- (trifluoromethylphenylmethylpiperidin-2-ylmethylcarbamate-tert -butyl) Synthesis of the title compound from methanesulfonate of [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl (Compound dd10) was performed under the same conditions as for Compound b7. However, fer-butyl / V - [[(2R) -piperidin-2-ylmethylcarbamate was used in place of ferric butyl / V - [(3R) -pyrrolidin-3-ylcarbamate, and DIPEA was used instead of TEA. [Example 428] Compound DD-35 4-rr (2R) -2- (aminomethylpiperidin-1-inmethyl-3-chloro- / V- (5-chloro-2-ethylsulfonylphenimethyl) -5- (trifluoromethyl) benzamide Synthesis of the title compound was carried out from N - [[(2R) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl ] piperidin-2-yl] methyl] carbamic acid (Compound dd 12) under the same conditions as for Compound B-1.
LCMS: m / z 566 [M + H] HPLC retention time: 0.55 min (analysis condition A) [Example 429] Compound dd13 / V-f3- -1 -ff2-chloro-4-r (5-chloro-2- Ethyl sulfonylphenyl) methylcarbamoyH-6- (trifluoromethyl) -phiHmethylpiperidin-2-y-methylamino-3-oxopropycarbamate-ferric acid Synthesis of the title compound was carried out from 4 - [[(2R) -2- (aminomethyl) piperidin-1-yl] methyl] -3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl)] methyl] -5- (trifluoromethyl) benzamide (Compound DD-35) under the same conditions as for Compound DD-1.
However, 3 - [(2-methylpropan-2-yl) oxycarbonylamino] propanoic acid was used in place of 1H-pyrrole-2-carboxylic acid, and HATU was used in place of HBTU.
[Example 430] Compound DD-36 4-ff (2R) -2-f (3-aminopropanoylamino) methynpiperidin-1-inmetn-3-chlorochlor-2-ethylsulfonylphenimmetin-5- (trifluoromethybenzamide The synthesis of the title compound was carried out from N- [3 - [[(2R) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin-2-yl] methylamino] - Ferd-butyl 3-oxopropyl] carbamate (Compound dd13) under the same conditions as for Compound B-1.
LCMS: m / z 637 [M + H] + HPLC retention time: 0.42 min (condition of F analysis) [Example 431] Compound DD-37 3-chloro-AM (5-chloro-2-ethylsulfonylphenimethyl-4-rr (2R) -2- (methylaminomethylpiperidjn-1-illmetin-5- (trifl uorome t i I) ben z amide The synthesis of the title compound was carried out from [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl methanesulfonate (Compound dd 10) under the same conditions as for Compounds dd 12 and DD-35. However, under the conditions of Compound dd 12, A / -methyl-A / - [[(2R) -piperidin-2-ylmethylcarbamate of fer-butyl was used instead of / V - [[(2R) -piperidin- 2- Ferric-butyl iljmetiljcarbamate.
LCMS: m / z 580 [M + H] + H PLC retention time: 0.60 min (condition of F analysis [Example 433] Compound dd14 A / -f2-f (3Sl-1 -ff2-chloro-4-r (5-chloro-2-ethylsulfonyl-phenemethylcarbamoyl-6- (trifluoromethylphenimethoxypiperidin-3-inoxylenedicarbamate benzyl Synthesis of the title compound from methanesulfonate of [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl (Compound dd 10) was performed under the same conditions as for Compound dd 1 1. However, A / - [2 - [(3S) -piperidin-3-yl] oxyethyl] benzyl carbamate was used in place of A / -ethyl- / V - [(3S) -piperidin-3-yl] carbamate of tere-butyl.
[Example 434] Compound DD-39 4-3- (2-aminoethoxy) piperidin-1-ylmethyl-3-chloro-f (5-chloro-2- ethylsulfonylphenyl) methyl1-5- (trifluoromethylbenzamide A solution of hydrogen bromide / 25% acetic acid (1 ml) was added to A / - [2 - [(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl)] methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin-3-yl] oxyethyl] benzyl carbamate (Compound dd 14, 23.0 mg, 0.0310 mmol); and was stirred at room temperature for two hours. The reaction mixture was made basic by adding a 5N aqueous solution of sodium hydroxide, and the aqueous layer was then extracted three times with DCM. The combined organic layers were dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (water / acetonitrile, 0.05% TFA) to yield the title compound (9.50 mg, 50%) as a colorless solid.
LCMS: m / z 596 [M + H] + HPLC retention time: 0.41 min (condition of F analysis) [Example 435] Compound DD-40 3-chloro- / V-f (5-chloro-2-ethylsulfonylphenyl) metin-4-rr (3S) -3- (2-hydroxyethoxy) piperidin-1-inmet-Ml-5- (trifluoromethyl) benzamide Synthesis of the title compound from methanesulfonate of [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl (Compound dd 10) was carried out under the same conditions as for Compound dd 1 1. However, the reaction was performed using 2 - [(3S) -piperidin-3-yl] oxyethanol instead of A / -ethyl-A / - [(3S) -piperidin-3- il] tert-butyl carbamate, and potassium carbonate was added.
LCMS: m / z 597 [M + H] HPLC retention time: 0.51 min (condition of F analysis) [Example 438] Compound dd15 / V-3-rr (3S) -1-rf2-chloro-4-f (5-chloro-2-ethylsulfonylphenyl) methylcarbamom-6- (trifluoromethyl) phenylmethylpiperidin-3-i of butyl-butyl Synthesis of the title compound was performed from 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] - 5- (trifluoromethyl) benzamide (Compound D-18) under the same conditions as for Compound H-5. However, urea-butyl (3-bromopropyl) carbamate was used in place of iodoethane.
[Example 439] Compound DD-43 4-ff (3S) -3- (3-aminopropylaminolpiperidin-1-methyn-3-chloro- / V-f (5-chloro-2-ethylsulfonylphenyl) methyl-5- (trifluoromethyl) benzamide Synthesis of the title compound was carried out from N- [3 - [[(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) feryl-butyl phenyl] methyl] piperidin-3-yl] amino] propyl] carbamate (Compound dd15) under the same conditions as for Compound B-1.
LCMS: m / z 609 [M + H] + H PLC retention time: 0.47 min (analysis condition F) [Example 440] Compound DD-44 3-chloro- / V-r (5-chloro-2-ethylsulfonylphenyl) metill-4-rr (3R) -3- (3-hydroxypropylpiperidin-1-inmetill-5- (trifluoromethyl) benzamide Synthesis of the title compound from methanesulfonate of [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl (Compound dd 10) was performed under the same conditions as for Compound dd 1 1. However, 3 - [(3R) -piperidin-3-yl] propan-1 -ol was used in place of fer-butyl N-ethyl-A / - [(3S) -piperidin-3-yl] carbamate.
LCMS: m / z 595 [M + H] + HPLC retention time: 0.53 min (condition of F analysis) [Example 441] Compound DD-45 4-R (3-aminopropylamino) methylene-3-chloro-AM (5-chloro-2-ethylsulfonylphenyl) metin-5- (trifluoromethylbenzamide Synthesis of the title compound from methanesulfonate of [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl (Compound dd 10) was performed under the same conditions as for Compound dd 1 1. However, the reaction was carried out at room temperature using 1,3-propanediamine instead of fer-butyl N-ethyl- / V - [(3S) -piperidin-3-yl] carbamate.
LCMS: m / z 526 [M + H] + HPLC retention time: 0.38 min (condition of F analysis) [Example 442] Compound DD-46 3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4 - [(2-oxo-1,3-diazinan-1-yl) methyl] -5- (trifluoromethyl) benzamide A solution of 4 - [(3-aminopropylamino) methyl] -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound DD-45, 15.0 mg, 28.0 pmol) and DIPEA (7.5 ml) in DCM (20 ml) was cooled to 0 ° C, a solution of 4-nitrophenyl chloroformate (5.90 mg, 29.0 pmol) in DCM (8 ml) was added, and the mixture was stirred for an hour. DIPEA (7.5 pl) was added, and the mixture was stirred at 0 ° C for 1.5 hours, at room temperature for three hours and under reflux for one hour. The reaction mixture was cooled to 0 ° C, a solution of 4-nitrophenyl chloroformate (1.90 mg, 9.00 pmol) in DCM (1 ml) was added, and the mixture was stirred at room temperature for one hour. After the addition of DMF (20 ml) to the reaction mixture, DCM was removed by concentration under reduced pressure, DIPEA (7.5 ml) was added, and the mixture was stirred at room temperature for 45 minutes. minutes and at 60 ° C for 40 minutes. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (water / acetonitrile, 0.05% TFA) to yield the title compound (9.50 mg, 60%) as a colorless foamy substance.
LCMS: m / z 552 [M + H] + HPLC retention time: 0.71 min (condition of F analysis) [Example 443] Compound DD-47 3-chloro-A / -r (5-chloro-2-ethylsulfonylphenyl) metin-4-rr3-r3- (dimethylamino) propylaminolpropylaminolmetiH-5- (trifluoromethylbenzamide) Synthesis of the title compound from methanesulfonate of [2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl (Compound dd 10) was performed under the same conditions as for Compound dd1 1. However, the reaction was carried out by using N '- (3-aminopropyl) -A /, / Vd i meti I-1, 3-propandiamine instead of A / -ethyl- / V - [(3S) -piperidin- 3-yl] tert-butyl carbamate and at temperature ambient.
LCMS: m / z 61 1 [M + H] + HPLC retention time: 0.34 min (condition of F analysis) [Example 444] Compound DD-48 3-chloro-A / -r (5-chloro-2-ethylsulfonylphenyl) methyl-1-4-rr3-r3- (dimethylamino) pro-Pili -2 -oxo-1,3-diazinan-1 -iMmetill-5- ( trifluoromethylbenzamide OR Synthesis of the title compound was carried out from 3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4 - [[3- [3- (di metílamin o) propi lamí no] propyl mino] methyl] -5- (trifluoromethyl) benzamide (Compound DD-47) under the same conditions as for Compound DD-46.
LCMS: m / z 637 [M + H] + H PLC retention time: 0.57 min (F analysis condition) [Example 445] Compound dd16 4- (Bromometin-3-chloro-A / -r (5-chloro-2-ethylsulfonylphenimethyl-5- (trifluoromethylbenzamide 3 chlorine A / [(5-chloro-2-ethylsulfonylphenyl) methyl] 4 (hydroxymethyl) -5- (trifluoromethyl) benzamide (Compound dd9, 165 mg, 0.351 mmol) and carbon tetrabromide (175 mg, 0.526 mmol) in THF (2 mL), and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (152 mg, 81%) as a solid. colorless.
LCMS: m / z 532 [M + H] + 15 PLC retention time: 0.95 min (analysis condition F) [Example 446] Compound dd17 AM2-fí (3S) -1-rr2-chloro-4-r (5-chloro-2-) -6-0 (trifluorometi Ofenillmetil 1 p i p e r i din-3 of fer-butyl 5 A / - [2 - [[(3S) -piperidin-3-yl] sulfamoyl] ethyl] ethylcarbamic acid ester (25.9 mg, 84.0 pmol) was added to a solution of 4- (bromomethyl) -3-chloro- A / - [(5-Chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd 16, 30.0 mg, 56.0 pmol) and potassium carbonate (23.3 mg, 0.169 mmol) in DMF (0.5 ml) , and the mixture was stirred at 50 ° C for two hours. The reaction mixture was cooled to room temperature and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (39.0 mg, 91%) as a colorless solid.
LCMS: m / z 759 [M + H] + HPLC retention time: 0.78 min (condition of F analysis) [Example 447] Compound DD-49 4-rf (3S) -3- (2-aminoethylsulfonylamino) pDerdin-1-methylmethin-3-chloro- / V- r (5-chloro-2-ethylsulfonyl-phenylimine-5- (trifluoromethyl) -benzamide) Synthesis of the title compound was carried out from N- [2 - [[(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin-3-yl] sulfamoyl] ethyl] carbamic acid ester (Compound dd17) under the same conditions as for Compound B-1.
LCMS: m / z 661 [M + H] + HPLC retention time: 0.49 min (condition of F analysis) [Example 448] Compound DD-50 3-chloro- / V-r (5-chloro-2-ethylsulfonylphenyl) metin-4-rr (3S) -3-r2- (dimethylamino) ethylsulfonylaminolpperidin-1-inmetill-5- (trifluoromethyl) benzamide Synthesis of the title compound was carried out from 4- (bromomethyl) -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5-20 (trifluoromethyl) benzamide (Compound dd16) under the same conditions as for Compound dd 17. However, 2- (dimethylamino) -A / - [(3S) -piperidin-3-yl] ethanesulfonamide was used in place of A / - [2 - [[(3S) - piperidin-3-yl] sulfamoyl] ethyl] tert-butyl carbamate.
LCMS 25: m / z 687 [M + H] HPLC retention time: 0.50 min (condition of F analysis) [Example 449] Compound dd18 / V-f2-ft3Rl-1 -ff2-chloro-4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamoH-6- (trifl uoromethyfen illmetinpi perid in-3-i Methyl benzyl ester Synthesis of the title compound was carried out from 4- (bromomethyl) -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd 16) under the same conditions as for Compound dd 17. However, A / - [2 - [(3R) -piperidin-3-yl] ethyl] benzyl carbamate was used instead of N- [2 - [[(3S) - piperidin-3-yl] sulfamoyl] ethyl] tere-butyl carbamate. [Example 450] Compound DD-51 4-if (3R) -3- (2-aminoethyl) piperidin-1-ylmet i P-3-cl gold - / \ M (5-cl prom etyl sulfonylphenimmethyl-5- (trifluoromethylbenzamide The synthesis of the title compound was carried out from N- [2 - [(3R) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] ] methyl] piperidin-3-yl] ethyl] benzyl carbamate (Compound dd18) under the same conditions as for Compound DD-39.
LC S: m / z 580 [M + H] + HPLC retention time: 0.42 min (condition of F analysis) [Example 451] Compound dd19 5-rr2-chloro-4-f (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-1- (2- trifluoromethyl-phenyl) -methyl-1,2-oxadiazepane-2-carboxylic acid Synthesis of the title compound was carried out from 4- (bromomethyl) -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd 16) under the same conditions as for Compound g3. However, 1, 2,5-oxadiazepane-2-carboxylic acid-butyl ester was used instead of piperazine-1-ferrobutyl carboxylate, and DM F was used instead of THF as a solvent.
[Example 452] Compound DD-52 3-Chloro-A / -f (5-chloro-2-ethylsulfonylphennillill-4- (1 .2.5-oxadiazeoan-5-i-Imet i) -5- (t rif lu prometi I) benza mida Synthesis of the title compound was performed from 5 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] -1, 2.5- ferd-butyl oxadiazepane-2-carboxylate (Compound dd 19) under the same conditions as for Compound B-1.
LCMS: m / z 554 [M + H] + HPLC retention time: 0.58 min (condition of F analysis) [Example 453] Compound dd20 (2S) -5- Chloro-4-r (5-chloro-2-ethylsulfonyl) -methylcarbamoyl-6 (t rifluo rometihfe niHmethylamino) -2-f (2-m ethyl tere-butyl-2-inoxocarbonylaminolpentanoate The synthesis of the title compound was carried out from (bromomethyl) -3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd 16) under the same conditions as for Compound g3. However, the reaction was performed using ferrous butyl (2S) -5-amino-2 - [(2-methylpropan-2-yl) oxycarbonylamino] pentanoate instead of piperazine-1-fer-butylcarboxylate and DMF instead of THF as a solvent.
[Example 454] Compound DD-53 4-rr (3S) -3-amino-2-oxopiperidin-1-ylmethyl-3-chloro-A / -f (5-chloro-2-ethylsulfonylphenyl) metin-5- (trifluoromethyl) benzamide An aqueous solution of 36% hydrochloric acid (149 ml) was added to a solution of (2S) -5 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) ) phenyl] methylamino] -2 - [(2-methylpropan-2-yl) oxycarbonylamino] pentanoate of fer-butyl (Compound dd20, 29.8 mg, 40.0 pmol) in 2,2,2-trifluoroethanol (750 pl); and was stirred at room temperature for one hour. The reaction mixture was diluted with 2,2,2-trifluoroethanol (2 mL) and toluene (5 mL), and then concentrated under reduced pressure. The resulting residue was dried by azeotropic distillation with toluene (5 ml x 2) to yield a crude product of (S) -2-amino-5 - ((2-chloro-4 - ((5-chloro-2- (ethylsulfonyl) benzyl) carbamoyl) -6- (trifluoromethyl) benzyl) amino) pentanoic acid dihydrochloride (32.8 mg ) as a pale yellow solid.
LCMS: m / z 584 [M + H] + HPLC retention time: 0.43 min (F analysis condition) (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (35.7 mg, 0.080 mmol) and DIPEA (35 ml) were added sequentially to a solution of the crude product of (S) -2-amino-5-dihydrochloride. ((2-Chloro-4 - ((5-chloro-2- (ethylsulfonyl) benzyl) carbamoyl) -6- (trifluoromethyl) benzyl) amino) pentanoic obtained above (32.8 mg) in DMF (2 mL); and stirred at room temperature for 30 minutes. Water (100 pl) was added to the reaction solution, and then the solvent was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (water / acetonitrile, 0.05% TFA) and silica gel column chromatography of amino (MeOH / DCM) to give the title compound (9.9 mg, 44%) as a colorless solid. .
LCMS: m / z 566 [M + H] + HPLC retention time: 0.52 min (condition of F analysis) [Example 455] Compound dd21 h / -G2-GG chloro-4-f (5-chloro-2- Ethyl-sulfonyl-phenylmethylcarbamom-6- (trifluoromethyl-phenylmethylpiperidine-3-carbonyl-tert-butyl carbamate) Synthesis of the title compound was carried out from 4- (bromomethyl) -3-chloro - / [- [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd 16) under the same conditions as for Compound dd 17. However, W- [2 - [[(3S) -piperidine-3-carbonyl] amino] ethyl] ferba-butyl carbamate was used instead of A / - [2- [[(3S) -piperidin-3-yl] sulfamoyl] ethyl] tere-butyl carbamate.
[Example 456] Compound DD-54 - / V- (2-aminoethyl) -1-rf2-chloro-4-f (5-chloro-2-ethylsulfonylphenimethylcarbamoyH-6- (trifluoromethyl) phenyl-1-methylpiperidine-3-carboxamide The synthesis of the title compound was carried out from N- [2 - [[(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-3-carbonyl] amino] ethyl ] ferd-butyl carbamate (Compound dd21) under the same conditions as for Compound B-1.
LCMS: m / z 623 [M + H] + H PLC retention time: 0.41 min (analysis condition F) [Example 457] Compound dd22 3-Chloro-4-formyl-5- (trifluoromethyl-P-benzoic acid) Synthesis of the title compound was carried out from ethyl 3-chloro-4-formyl-5- (trifluoromethyl) benzoate (Compound d7) under the same conditions as for Compound b8. However, an aqueous 5N sodium hydroxide solution was used instead of a 1 N aqueous sodium hydroxide solution.
[Example 458] Compound dd23 3-chloro-A / -ph5-chloro-2-ethylsulfonylphenimetin-4-formyl-5- (trifluoromethyl) benzamide Synthesis of the title compound was carried out from 5-chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, the reaction was performed by using 3-chloro-4-formyl-5- (trifluoromethyl) benzoic acid (Compound dd22) instead of 4 - [[4- [(2-methylpropan-2-yl) oxycarbonyl]] piperazin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3) as a carboxylic acid, and acetonitrile in place of DM F as the solvent.
[Example 459] Compound dd24 A / -f (3S) -1 -rr2-chloro-4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-1-6- (trifluoromethyl) phenymethyl-pyrrolidin-3-tert-butylcarbamate Synthesis of the title compound was carried out from 3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-5- (trifluoromethyl) benzamide (Compound dd23) under the same conditions as for Compound b32. However, ferc-butyl / V - [(3S) -pyrrolidin-3-yl] carbamate was used in place of ferrubutyl N- [[(2S) -pyrrolidin-2-yl] methyl] carbamate, and chloroform was used instead of THF as the solvent. The reaction was carried out at a reaction temperature of 0 ° C.
[Example 460] Compound DD-55 4-rf (3S) -3-aminopyrrolidin-1 -illmetin-3-chloro- / V-r (5-chloro-2-ethylsulfonylphenyl) metin-5- (trifluoromethyl) benzamide Synthesis of the title compound was carried out from N- [(3 S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl ] Ferric-butyl pyrrolidin-3-ylcarbamate (Compound dd24) under the same conditions as for Compound B-57.
LCMS: m / z 538 [M + H] + HPLC retention time: 0.49 min (condition of F analysis) [Example 461] Compound DD-56 4- [i (3R) -3- (Aminomethylpiperidin-1-iHmethyl-3-chloro- / V-r (5-chloro-2-ethylsulfonylphenimmetin-5- (trifluoromethylbenzamide Synthesis of the title compound was carried out from 3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-5- (trifluoromethyl) benzamide (Compound dd23) under the same conditions as for Compounds dd24 and DD-55. However, under the conditions of Compound dd24, N - [[(3S) -piperidin-3-yl] methyl] carbamate / butyl-butyl was used in place of N - [(3S) -pyrrolidin-3-yl] Ferric butyl carbamate.
LCMS: m / z 566 [M + H] + HPLC retention time: 0.42 min (condition of F analysis) [Example 462] Compound dd25 3-chloro-4-rr3-r (2-methylpropan-2-iPoxicarbonilamino] azetidin-1 -iHmetin-5- (ethyl trifluoromethylbenzoate Synthesis of the title compound was carried out from ethyl 3-chloro-4-formyl-5- (trifluoromethyl) benzoate (Compound d7) under the same conditions as for Compound b32. However, tere-butyl / tert-butyl (/ azetidin-3-yl) carbamate was used in place of tere-butyl / V - [[(2S) -pyrrolidin-2-yl] methyl] carbamate, and was used DCM instead of THF as a solvent.
[Example 463] Compound dd26 3-Chloro-4- [f3-r (2-methylpropan-2-yloxycarbonylamino] azetidin-1-inmet-H-5- (trifluoromethyl) benzoic acid Synthesis of the title compound was performed from 3-chloro-4 - [[3 - [(2-methylpropan-2-yl) oxycarbonylamino] azetidin-1-yl] methyl] -5- (trifluoromethyl) benzoate of ethyl (Compound dd25) under the same conditions as for Compound b8.
[Example 464] Compound dd27 / V-f1 -ff2-chloro-4-r (5-chloro-2-ethylsulfonylphenimethylcarbamoyl) -6- (trifluoromethyl-phenylaminetidin-3-ylcarbamate (e-butyl) Synthesis of the title compound was carried out from 5-chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, 3-chloro-4 - [[3 - [(2-methylpropan-2-yl) oxycarbonylamino] azetidin-1-yl] methyl] -5- (trifluoromethyl) benzoic acid was used.
(Compound dd26) in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1 -i I] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3) as an acid carboxylic [Example 465] Compound DD-57 4-F (3-aminoazetidin-1-inmetin-3-chloro-A / -r (5-chloro-2-ethi ls u Ifo n Ife nil) metí M-5- (triflu oro metí Dbenza mida The synthesis of the title compound was carried out from N- [1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] azetidin-3- il] butyl-butyl carbamate (Compound dd27) under the same conditions as for the Compound B-57.
LCMS: m / z 524 [M + H] + HPLC retention time: 1 .10 min (analysis condition D) [Example 466] Compound DD-58 3-chloro-A / -f (5-chloro-2-ethylsulfonylpheniDmetiH-4-rf3- (methylsulfamoylamino) azetidin-1-inmetin-5- (trifluoromethylbenzamide TEA (23 ml, 0.166 mmol) was added to a solution of 4 - [(3-aminoazetidin-1-yl) methyl] -3-chloro- / V - [(5-chloro-2- ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound DD-57, 28.9 mg, 0.0496 mmol) and / V-methy1-2-oxo-1,3-oxazolidine-3-sulfonamide (15.3 mg, 0.0849 mmol) in acetonitrile (1 mL); and stirred at 65 to 80 ° C for one hour. The reaction solution was cooled to room temperature, followed by the addition of water and extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (20.0 mg, 65%) as a colorless solid. However, A / -methyl-2-oxo-1,3-oxazolidine-3-sulfonamide was synthesized following the method described in WO 2009080638.
LCMS: m / z 617 [M + H] + HPLC retention time: 1.48 min (analysis condition D) [Example 467] Compound DD-59 3-chloro- / V-((5-chloro-2-ethylsulfonylphenimethyl-4-fr3- (dimethylsulphamoylamino) azetidin-1-inmetin-5- N, N-Dimethylsulfamoyl chloride (17.3 mg, 0.121 mmol) and TEA (34.0 mL, 0.241 mmol) were added to a solution of 4 - [(3-aminoazetidin-1-yl) methyl] -3-chloro- / V - [(5-Chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound DD-57, 39.7 mg, 0.0603 mmol) in DM F (0.5 ml) cooled with ice; and was warmed to room temperature and stirred for 2.5 hours under a nitrogen atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed with brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (22.6 mg, 59%) as a colorless solid.
LCMS: m / z 631 [M + H] + H PLC retention time: 1.45 min (analysis condition D) [Example 468] Compound dd28 / V-rn -rr2-chloro-4-f (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-6- (trifluoromethyl) phenemetinazetidin-3-insulfamomcarbamate-butyl ester The title compound was synthesized from 4 - [(3-aminoazetidin-1-yl) methyl] -3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound DD-57) under the same conditions as for Compound DD-58. However, / V- (tert-butoxycarbonyl) - / V- [4- (dimethMazanioylidene) -1,4-dihydropyridin-1-ylsulfonyl] azanide was used in place of N-methyl-2-oxo-1, 3-oxazolidine-3-sulfonamide.
N- (ferc-Butoxycarbonyl) - / \ / - [4- (dimethylazanioylidene) -1,4-dihydropyridin-1-ylsulfonyl] azanide was synthesized according to the method described in the literature (Organic Letters, vol.3, pp 2241-2243, 2001).
[Example 469] Compound DD-60 3-chloro- / V-r (5-chloro-2-ethylsulfonylphenyl) metill-4-fr3- (sulfamoylaminolazetidin-1 - Hmetin-5- (trifluoromethyl) benzamide The title compound was synthesized from N - [[1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] azetidin-3 -yl] sulfamoyl] tert-butyl carbamate (Compound dd28) under the same conditions as for Compound B-57.
LCMS: m / z 603 [M + H] + HPLC retention time: 1.32 min (condition of analysis D) [Example 470] Compound dd29 3-Chloro-4-y4 - [(2-methylpropan-2-yl-oxo-carbonylaminolpiperidin-1-methyl-5- (ethyl trifluoromethylbenzoate title post from ethyl 3-chloro-4-formyl-5- (trifluoromethyl) benzoate (Compound d7) under the same conditions as for Compound b32. However, terebutyl / V-piperidin-4-ylcarbamate was used in place of ferrubutyl N- [[(2S) -pyrrolidin-2-yl] methyl] carbamate, and chloroform was used instead of THF as solvent.
[Example 471] Compound dd30 3-chloro-4-fí4-f (2-methylpropan-2-yloxycarbonylaminolpiperidin-1-methylmethyl-5- (trifluoromethylbenzoic acid The title compound was synthesized from ethyl 3-chloro-4 - [[4- [(2-methyl-propane-2-yl) oxycarbonylamino] piperidin-1-yl] methyl] -5- (trifluoromethyl) benzoate (Compound dd29) under the same conditions as for Compound b8.
[Example 472] Compound dd31 N- f 1-chloro-4-r (5-chloro-2-ethylsulfonylphenimethylcarbamoyl) -6- tere-butyl (trifluoromethyl) phenephyrimperidin-4-illcarbamate The title compound was synthesized from 5- chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compound A-14. However, 3-chloro-4 - [[4 - [(2-methylpropan-2-yl) oxycarbonylamino or] pipe ridin-1-yl] methyl] -5- (trifluoromethyl) benzoic acid (Compound dd30) was used in place of 4-bromo-3- (trifluoromethyl) benzoic acid as a carboxylic acid, and DCM was used in place of DM F as the solvent.
[Example 473] Compound DD-61 4-rf4-aminopiperidin-1 -ihmetin-3-chloro- / V-f (5-chloro-2-ethylsulfonylphenyl) metin-5- (trifluoromethyl) benzamide The title compound was synthesized from A / - [1 - [[2-chloro- 4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin-4-yl] carbamic acid ester (Compound dd31) under the same conditions as for Compound B-57 .
LCMS: m / z 552 [M + H] HPLC retention time: 0.44 min (condition of F analysis) [Example 474] Compound dd32 A / -f2-r4-IT2-chloro-4-r (tert-butyl 5-chloro-2-et-M-sulfonyl-phenemet -carbamom-6- (trifluoromethyl-phenylperazin-1-yH-2-oxoetylcarbamate) The title compound was synthesized from 3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1 -i methyl) -5- (trifluoromethyl) benzamide (Compound D -1) under the same conditions as for Compound DD-1. However, the reaction was performed by using 2 - [(2-methylpropan-2-yl) oxycarbonylamino] acetic acid in place of 1H-pyrrole-2-carboxylic acid and by using HATU instead of HBTU.
[Example 475] Compound DD-62 4-r [4- (2-aminoacetyl) piperazin-1-illmethyl-3-chloro- / N / -r (5-chloro-2-ethylsulfonyl-phenyl) -methyl-5- (trifluoromethyl) -benzamide A solution of 4N / 1,4-dioxane hydrochloric acid (0.9 ml) was added to a solution of A / - [2- [4 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl ] -6- (trifluoromethyl) phenyl] methyl] piperazin-1-yl] -2-oxoethyl] carbamate ferd-butyl (Compound dd32, 61 mg, 0.088 mmol) in DCM (0.9 ml), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by chromatography on an amino silica gel column (MeOH / DCM) to yield the title compound (35 mg, 67%) as a colorless solid.
LCMS: m / z 595 [M + H] + HPLC retention time: 0.53 min (condition of F analysis) [Example 476] Compound DD-63 3-chloro-A / -f (5-chloro-2-ethylsulfonylphenyl) methyl-4-fí4- (2-hydroxyacetyl) piperazin-1-immethin-5- (trifluoromethyl) benzamide The title compound was synthesized from 3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide (Compound D-1 ) under the same conditions as for Compound DD-1. However, the reaction was performed by using 2-hydroxyacetic acid instead of 1 H-pyrrole-2-carboxylic acid and by using HATU instead of HBTU.
LCMS: m / z 596 [M + H] + H PLC retention time: 0.68 min (F analysis condition) [Example 477] Compound DD-64 3-chloro- / V-f (5-chloro-2-ethylsulfonylphenimmetin-4-rf4- (2-hydroxyethylpiperazin-1-iHmetin-5- (trifluoromethylbenzamide The title compound was synthesized from 3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide (Compound D-1 ) under the same conditions as for Compound H-5. However, 2-bromoethanol was used instead of iodoethane. The reaction was carried out with the addition of triethylamine.
LCMS: m / z 582 [M + H] + HPLC retention time: 0.54 min (condition of F analysis [Example 478] Compound dd33 3-clo ro-3-rmethyl-r (2-m ethylpro pano li) oxycarbo ni Ha mino! pipe rid i n-1 -i 11 metí M-5- (triflu promised!) ethyl benzoate The title compound was synthesized from ethyl 3-chloro-4-formyl-5- (trifluoromethyl) benzoate (Compound d7) under the same conditions as for Compound b32. However, A / -methyl- / V - [(3S) -piperidin-3-yl] -erc-butyl carbamate was used in place of (S) -1-pyrrolidin-2-ylmethyl-carbamic acid fer-butyl ester. .
[Example 479] Compound dd34 Acid _ 3-chloro-4-rr (3S) -3-rmethyl-r (2-methylpropan-2-inox -carboninamino-piperidin-1-inmetin-5- (trifluoromethyl-benzoic acid The title compound was synthesized from 3-chloro-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5 - (ethyl trifluoromethyl) benzoate (Compound dd33) under the same conditions as for Compound b8 [Example 480] Compound dd35 5-clo ro-2-r ro pilsulfa nil be nzo nitrite tetized the title compound from 5-chloro-2- nitrile under the same conditions as for Compound a1. However, propane-1-thiol was used in place of ethanethiol.
[Example 481] Compound dd36 (5 l 2 phenylsulfanylphenyl) methanamine The title compound was prepared from 5-chloro-2-propylsulfanylbenzonitrile (Compound dd35) under the same conditions as for Compound a2.
[Example 482] Compound dd37 (5-Chloro-2-propylsulphonylphenolimene in my hydrochloride .
The title compound was synthesized from (5-chloro-2-propylsulfanylphenyl) methanamine (Compound dd36) under the same conditions as for Compound a3.
[Example 483] Compound dd38 / V- -1 -ff2-chloro-4-y (5-chloro-2- propylsulfonylphenyl) methylcarbamoyH-6- (trifluoromethylpheninmethylpiperidin-3-ill-A / tere-butyl methylcarbamate) The title compound was synthesized from (5-chloro-2-propylsulfonylphenyl) methanamine hydrochloride (Compound d37) under the same conditions as for Compound A-14. However, 3-chloro-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5- (trifluoromethyl) acid was used. ) benzoic (compound dd34) instead of 4-bromo-3-trifluoromethyl-benzoic acid.
[Example 484] Compound DD-65 3-chloro-A / -f (5-chloro-2-propylsulfonylphenyl) metill-4-fr -3- (methylamino) piperidin-1 -illmetin-5-urafluoromethylbenzamide The title compound was synthesized from N - [(3S) -1 - [[2-chloro-4 - [(5-chloro-2-propylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin- 3-yl] -A-tert-butyl methylcarbamate (Compound dd38) under the same conditions as for Compound B-1.
LCMS: m / z 580 [M + H] + HPLC retention time: 0.59 min (condition of F analysis) [Example 485] Compound dd39 (5-chloro-2-phenylsulfanylphenyl) methanamine The title compound was synthesized from 5-chloro-2-fluorobenzonitrile under the same conditions as for Compounds dd35 and dd36. However, benzenethiol was used in Place of propane-1-thiol under the conditions of Compound dd35. [Example 486] Compound dd40 R2- (benzenesulfonyl-5-chlorophenemethanamine hydrochloride) The title compound was synthesized from (5-chloro-2-phenylsulfanylphenyl) methanamine (Compound dd39) under the same conditions as for Compounds a9, a 10 and a 1 1. However, the reaction was carried out under the conditions of Compound a9 with the addition of triethylamine.
[Example 487] Compound DD-66 N- (benzenesulfonyl) -5-chloro-phenyl-3-chloro-4-yl (3S) -3- (methylamino) piperidin-1-inmethyl-5- (trifluoromethyl-benzamide) The title compound was synthesized from [2- (benzenesulfonyl) -5-chlorophenyl] methanamine hydrochloride (Compound dd40) under the same conditions as for Compounds dd38 and DD-65.
LCMS: miz 614 [M + H] + HPLC retention time: 0.61 min (condition of F analysis) [Example 488] Compound DD-67 3-chloro-A / -r (5-chloro-2-propan-2-ylsulfonyl-phenylemin-4-rr (3St-3- (methylaminolpiperidin-1-inmetill-5- (trifluoromethyl) benzamide The title compound was synthesized from 5-chloro-2-fluorobenzonitrile under the same conditions as for Compounds dd35, dd36, dd37, dd38 and DD-65. However, propane-2-thiol was used instead of propane-1-thiol under the conditions of dd35.
LCMS: m / z 580 [M + H] + HPLC retention time: 0.60 min (condition of F analysis) [Example 489] Compound dd41 (4-chloro-2-formyl-6-methoxy-phenyl-1-trifluoromethanesulfonate Trifluoromethylsulfonyl trifluoromethanesulfonate (688 mg, 2.44 mmol) was added to a solution of 5-chloro-2-hydroxy-3-methoxybenzaldehyde (403 mg, 2.16 mmol) in pyridine (7 mL), and stirred under ice cooling for 30 minutes. minutes under a nitrogen atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (648 mg, 94%) as a Oily substance pale yellow.
LCMS: m / z 319 [M + H] + HPLC retention time: 0.87 min (analysis condition A) [Example 490] Compound dd42 5-chloro-2-ethylsulfanyl-3-methoxybenzaldehyde Tris (dibenzylideneacetone) dipalladium (0) (66.8 mg, 0.0729 mmol), (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl) -diphenyl-phosphine (83.9 mg, 0.145 mmol), DIPEA (0.362 mL, 2.13 mmol) were added. ) and ethanethiol (0.210 ml, 2.84 mmol) to a solution of (4- chloro-2-formyl-6-methoxyphenyl) trifluoromethanesulfonate (Compound dd41, 319 mg, 0.709 mmol) in 1,4-dioxane (2.5 ml), and stirred at 100 ° C for 15 minutes. The reaction solution was cooled to room temperature, followed by the addition of water and extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (135 mg, 83%) as a yellow oily substance.
LCMS: m / z 231 [M + H] + HPLC retention time: 2.64 min (analysis condition D) [Example 491] dd43 o-2-ethylsulfanyl-3-methoxyphenin-A / -methoxymethane imine The title compound was synthesized from 5-chloro-2-ethylsulfanyl-3-methoxybenzaldehyde (Compound dd42) under the same conditions as for Compound a7.
[Example 492] Compound dd44 (5-Chloro-2-ethylsulfanyl-3-methoxyphenemethanamine) s synthesized the title compound from (E) -1- (5-chloro-2-ethylsulfanyl-3-methoxyphenyl) -A / -methoxymethanimine (Compound dd43) under the same conditions as for Compound a8. [Example 493] Compound dd45 Hydrochloride of (5-chloro-2-ethylsulfonyl-3-methoxyphenimethanamine) l Boc20 (121 mg, 0.553 mmol) was added to a solution of (5-chloro-2-ethylsulfanyl-3-methoxyphenyl) methanamine (Compound dd44, 105 mg, 0.452 mmol) and TEA (94.0 mL, 0.678 mmol) in THF ( 1.5 mi), and stirred at room temperature for 30 minutes under a nitrogen atmosphere. An aqueous solution of 10% citric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, a crude product of tere-butyl A / - [(5-chloro-2-ethylsulfanyl-3-methoxyphenyl) methyl] carbamate (182 mg) was obtained as a gray solid by concentration under pressure reduced.
To a solution of the crude product resulting from N- [. { Tere-Butyl 5-chloro-2-ethylsulfanyl-3-methoxyphenyl) methyl] carbamate (148 mg) in EtOAc (1.5 mL), m-CPBA (233 mg, 0.876 mmol) was added under ice-cooling, and it was warmed to room temperature and stirred for 30 minutes under a nitrogen atmosphere. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, a crude product of tere-butyl N - [(5-chloro-2-ethylsulfonyl-3-methoxyphenyl) methyl] carbamate was obtained by concentration under reduced pressure.
A solution of 4N hydrochloric acid / ethyl acetate (0.760 ml, 3.04 mmol) was added to the crude product of tere-butyl N - [(5-chloro-2-ethylsulfonyl-3-methoxyphenyl) methyl] carbamate_ obtained above in MeOH EtOAc (60 ml / 0.75 ml), and stirred at 60 ° C for three hours. The reaction solution was cooled to room temperature, and the precipitated solid was then washed with ethyl acetate to yield the title compound (99.8 mg, 90%) as a colorless solid.
LCMS: m / z 264 [M + H] + HPLC retention time: 0.59 min (condition of analysis D) [Example 494] Compound dd46 / V-r (3S) -1-rr2-chloro-4-f (5-chloro-2-ethylsulfonyl-3-methoxyphenemetylcarbamoyl-6- (trifluoromethyl-phenylmethylpiperdin-3-y-methyl butylcarbamate) The title compound was synthesized from hydrochloride (5-chloro-2-ethylsulfonyl-3-methoxyphenyl) methanamine (Compound dd45) under the same conditions as for Compound bb10. However, 3-chloro-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5- (trifluoromethyl) acid was used. ) benzoic (Compound dd34) in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1 -i I] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3).
[Example 495] Compound DD-68 3-chloro-A / -r (5-chloro-2-ethylsulfonyl-3-methoxyphenimmetin- -3- (methylamino) piperidin-l-inmetiN-5- (trifluoromethyl) benzamide The title compound was synthesized from / V - [(3S) -1 - [[2- Chloro-4 - [(5-chloro-2-ethylsulfonyl-3-methoxyphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin-3-yl] - / N / -methylcarbamate tert -butyl (Compound dd46) under the same conditions as for Compound B-57.
LCMS: m / z 596 [M + H] + HPLC retention time: 1.43 min (analysis condition D) [Example 496] Compound dd47 2-vodo-4,5-dimethylaniline Iodine (2.06 g, 8.1 1 mmol) in 10 parts was added to a mixed solution of 3, 4-dimethylaniline (893 mg, 7.37 mmol) and sodium bicarbonate (683 mg, 8.14 mmol) in MeOH / water (7 ml / 7 ml), and stirred at room temperature for one hour under a nitrogen atmosphere. Followed by the addition of water to the reaction mixture and extraction with dichloromethane, the organic layer was then washed with a saturated aqueous solution of sodium thiosulfate and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (1.54 g, 85%) as a brown solid.
LCMS: m / z 248 [M + H] + HPLC retention time: 1.91 min (condition of analysis D) [Example 497] Compound dd48 2-amino-4,5-dimethylbenzonitrile Copper cyanide (1) (1.24 g, 12.4 mmol) was added to a solution of 2-iodo-4,5-dimethylaniline (Compound dd46, 1.53 g, 6.21 mmol) in DMF (20 mL), and it was stirred at 150 to 160 ° C for 1.5 hours. After the reaction solution was cooled to room temperature, an aqueous solution of 10% ammonia (30 ml) and DCM (30 ml) was added, followed by removal of the insoluble matter by filtration through celite, and washed with DCM. The organic layer of the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield the title compound (796 mg, 88%) as a solid of color Brown.
LCMS: m / z 147 [M + H] HPLC retention time: 0.66 min (analysis condition A) [Example 498] Compound dd49 2-vodo-4,5-dimethylbenzonitrile Sodium nitrite (392 mg, 5.68 mmol) dissolved in water (2 ml) was added to a solution of 2-amino-4,5-dimethylbenzonitrile (Compound dd48, 682 mg, 4.67 mmol) in 2, 2.2 -trifluoroethanol / TFA (27 ml / 2.7 ml), and stirred at room temperature under a nitrogen atmosphere. After 20 minutes, potassium iodide (2.30 g, 13.9 mmol) was added, and further stirred for 1.5 hours. Followed by the addition of water to the reaction mixture and extraction with ethyl acetate, the organic layer was then washed with a saturated aqueous solution of sodium thiosulfate and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (694 mg, 58%) as a pale yellow solid.
LCMS: m / z 258 [M + H] + HPLC retention time: 0.85 min (analysis condition A) [Example 499] Compound dd50 2-ethylsulfanyl-4,5-imethylbenzonitrile The title compound was synthesized from 2-iodo-4,5-dimethylbenzonitrile (Compound dd49) under the same conditions as for Compound dd42.
[Example 500] Compound dd51 (2-ethylsulfanyl-4,5-dimethylphenmetamine namine The title compound was synthesized from 2-ethylsulfanyl-4,5-dimethylbenzonitrile (Compound dd50) under the same conditions as for Compound a2.
[Example 501] Compound DD-69 3-Chloro-A / -f (5-Chloro-2-ethylsulfonyl-3-methoxyphenylmetH-4-rr (3S) -3- (methylaminolpDeridin-1-H-Hetin-5- (trifluoromethylbenzamide The title compound was synthesized from (2-ethylsulfanyl-4,5-dimethylphenyl) methanamine (Compound dd51) under the same conditions as for Compounds dd44, dd45, dd46 and DD-68.
LCMS: m / z 560 [M + H] + HPLC retention time: 1.51 min (analysis condition D) [Example 502] Compound DD-70 3-chloro-A / -i (5-chloro-2-ethylsulfonyl-4-methylphenimethyl-4- [i -3- (methylamino) piperidin-1-iHmethyl-5- (trifluoromethylbenzamide The title compound was synthesized from 5-chloro-2-hydroxy-4-methylbenzaldehyde under the same conditions as for Compounds dd41, dd42, dd43, dd44, dd45, dd46 and DD-68. However, under Compound dd42 conditions, the reaction was carried out at a temperature of 80 ° C.
LCMS: m / z 580 [M + H] HPLC retention time: 0.59 min (analysis condition A) [Example 503] Compound dd52 of methyl The title compound was synthesized from methyl 3-chloro-4- (hydroxymethyl) -5- (trifluoromethyl) benzoate (Compound dd7) under the same conditions as for Compound dd16. [Example 504] Compound dd53 4-r (3-aminophenyl) methyl-1,3-chloro-5- (methyl trifluoromethylbenzoate The title compound was synthesized from methyl 4- (bromomethyl) -3-chloro-5- (trifluoromethyl) benzoate (Compound dd52) under the same conditions as for Compound bb1.
[Example 505] Compound dd54 4- f (3-a m i noten il) metin-3-chloro-5- (trifluoro methyl) benzoic acid The title compound was synthesized from methyl 4 - [(3-aminophenyl) methyl] -3-chloro-5- (trifluoromethyl) benzoate (Compound dd53) under the same conditions as for Compound b8. However, methanol was used in place of ethanol as the solvent.
[Example 506] Compound DD-71 4-ft3-aminophenimethyl-3-chloro-A / -f (5-chloro-2-ethylsulfonylphenol) metin-5- (trifluoromethyl-benzamide) The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound A-21. However, 4 - [(3-am i nofen i l) methyl] -3-chloro-5- (trifluoromethyl) benzoic acid was used.
(Compound dd54) in place of 3- (trifluoromethyl) benzoic acid.
LCMS: m / z 545 [M + H] + HPLC retention time: 0.81 min (condition of analysis F) [Example 507] Compound dd55 4- [f2-Chloro-4-methoxycarbonyl-6- (trifluoromethylphenylmethin-3,6-dihydro-2H-pyridine-1-tert-butylcarboxylate) The title compound was synthesized from methyl 4- (bromomethyl) -3-chloro-5- (trifluoromethyl) benzoate (Compound dd52) under the same conditions as for Compound bb1. However, 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert -butyl ester was used instead of (3-aminophenyl) boronic acid.
[Example 508] Compound dd56 4- Chloro-4-methoxycarbonyl-6- (trifluoromethylphenemethylpiperidine-1-carboxylic acid-butyl ester) The title compound was synthesized from 4 - [[2-chloro-4-methoxycarbonyl-6- (trifluoromethyl) phenyl] methyl] -3,6-dihydro-2H-pyridine-1-ferrobutylcarboxylate (Compound dd55) under the same conditions as for Compound bb4.
[Example 509] Compound dd57 3-Chloro-4-rf 1 -r (2-methylpropan-2-ylcarboniHpiperidin-4-yl II methyl-5- (triflu or romethyl) benzoic acid The title compound was synthesized from 4 - [[2-chloro-4-methoxycarbonyl-6- (trifluoromethyl) phenyl] methyl] piperidine-1-fer-butylcarboxylate (Compound dd56) under the same conditions as for the Compound b8. However, methanol was used instead of ethanol as the solvent.
[Example 510] Compound dd58 4-rf2-chloro-4-r (5-chloro-2-ethylsulfonylphenimethylcarbamom-6- (trifluoromethyl) phenylmethylpiperidine-l-tert-butylcarboxylate) The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound A-21. However, 3-chloro-4 - [[1 - [(2-methylpropan-2-yl) oxycarbonyl] piperidin-4-yl] methyl] -5- (trifluoromethyl) benzoic acid (Compound dd57) was used instead of 3- (trifluoromethyl) benzoic acid. [Example 51 1] Compound DD-72 3-chloro- / V-((5-chloro-2-ethylsulfonylpheniDmetiH-4- (pperiodin-4-ylnrythyl) -5- (trifluoromethylbenzamide l The title compound was synthesized from 4 - [[2-chloro-4- [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-1-ferrobutylcarboxylate 5 (Compound dd58) under the same conditions as for Compound B-1.
LCMS: m / z 537 [M + H] + HPLC retention time: 0.56 min (condition of F analysis) I [Example 512] Compound ee1 4-rr2-bromo-4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamom-6- (trifluoromethylphenylmethylpiperazine-1-tert-butylcarboxylate) The title compound was synthesized from 3-bromo- / V- [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-5- (trifluoromethyl) benzamide (Compound e7) under the same conditions as for the Compound b32. However, piperazine-1-fer-butylcarboxylate was used in place of ferric butyl (S) -1-pyrrolidin-2-ylmethyl-carbamate, and chloroform was used instead of THF as a solvent.
[Example 513] Compound EE-1 3-bromo - / \ M (5-chloro-2- -4- (piperazin-1-ylmethyl) -5- (trifluoromethyl-P-benzamide The title compound was synthesized from 4 - [[2-bromo-4- [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperazine-1-ferrobutylcarboxylate (Compound ee1) under the same conditions as for Compound B-57.
LCMS: m / z 582 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 514] Compounds EE-2 and EE-3 were synthesized from 3-bromo-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-5- (trifluoromethyl) benzamide (Compound e7) under the Same conditions as for Compound b32. However, 1-methylpiperazine was used in place of ferricbutyl (S) -1-pyrrolidin-2-ylmethylcarbamate, and chloroform was used in place of THF as the solvent.
Compound EE-2 3-bromo-AH (5-chloro-2-ethylsulfonylphenimethiN-4-r (4-methylpiperazin- 1 - . 1 -iPmetill-5- (trifluoromethylbenzamide LCMS: m / z 596 [M + H] + H PLC retention time: 0.53 min (analysis condition A) Compound EE-3 3-bromo- / V-r (5-chloro-2-ethylsulfonylphenyl) methyl-4- (hydroxymethyl) -5- (trifluoromethylbenzamide LCMS: m / z 514 [M + H] + HPLC retention time: 0.73 min (analysis condition A) [Example 515] Compound EE-4 4-rf (3S) -3-aminopyrrolidin-1-inmetn-3-bromo-f (5-chloro-2- Ethylsulfonylphenimethyl-5- (trifluoromethylphenamide) The title compound was synthesized from 3-bromo-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-5- (trifluoromethyl) benzamide (Compound e7) under the same conditions as for the Compounds ee1 and EE-1. However, under the conditions of Compound ee1, tere-butyl N - [(3S) pyrrolidin-3-yl] carbamate was used in place of the piperazine-1-carboxylic acid-butyl ester.
LCMS: m / z 582 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 516] Compound EE-5 3-bromo-A / -r (5-chloro-2-ethylsulfonyl-phenylimmet-4-rf (3S) -3- (methylamino) pyrrolidin-1-trimethoxy-5- (trifluoromethyl-P-benzamide p this title from 3-bromo- / V- [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-5- (trifluoromethyl) benzamide (Compound e7) under the same conditions as for Compounds ee1 and EE-1. However, under the conditions of Compound ee1, tere-butyl A / -methyl- / V - [(3S) -pyrrolidin-3-yl] carbamate was used in place of piperazine-1 - ferric butyl carboxylate.
LCMS: m / z 596 [M + H] + HPLC retention time: 0.53 min (analysis condition A) [Example 517] Compound ee2 / V-r2-f 1-rf2-bromo-4-f (5-chloro-2- ethylsulfonylphenyl) methylcarbamoyl-6- (tert-butyl trifluoromethylphenimethylnipperidin-3-ylamino-1-oxoetincarbamate) The title compound was synthesized from 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-bromo- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound E-3) under the same conditions as for Compound DD-1. However, 2 - [(2-methylpropan-2-yl) oxycarbonylamino] acetic acid was used in place of 1 H-pi-rrol-2-carboxylic acid, and HATU was used in place of HBTU as a condensing agent.
[Example 518] Compound EE-6 4-rf (3S) -3-r (2-aminoacetinaminolPiperidin-1 -illmetin-3-bromo-A / - r (5-chloro-2-ethylsulfonylphenimethyl-5- (trifluoromethylbenzamide The title compound was synthesized from N- [2 - [[(3S) -1 - [[2-bromo-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin-3-yl] amino] -2-oxoethyl] carbamic acid ester (Compound ee2) under the same conditions as for Compound B-57.
LCMS: m / z 653 [M + H] + HPLC retention time: 0.45 min (condition of analysis A) [Example 519] Compound EE-7 3-bromo-A / -i (5-chloro-2-ethylsulfonylphenimethyl-4-ry (3S) -3-fr2- (methylamino) acetinaminolpiperidin-l-illmethyl-5- (trifluoromethyl-benzamide The title compound was synthesized from 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-bromo-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound E-3) under the same conditions as for Compounds ee2 and EE-6. However, under the conditions of Compound ee2, 2- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] acetic acid was used in place of 2 - [(2-methylpropan-2-yl) oxycarbonylamino acid ]acetic.
LCMS: m / z 667 [M + H] + HPLC retention time: 0.46 min (analysis condition A) [Example 520] Compound EE-8 -3- (3-aminopropanoylamino) piperidin-1-inmethyl-3-bromo- / V- f (5-chloro-2-ethylsulfonylphenimetin-5- (trifluoromethylbenzamide The title compound was synthesized from 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-bromo - / [- [(5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benzamide (Compound E-3) under the same conditions as for Compounds ee2 and EE-6. However, under the conditions of Compound ee2, 3 - [(2-methylpropan-2-yl) oxycarbonylamino] propanoic acid was used in place of 2 - [(2-methylpropan-2-yl) oxycarbonylamino] acetic acid.
LCMS: m / z 667 [M + H] + HPLC retention time: 0.44 min (analysis condition A) [Example 521] Compound gg1 N - (2-bromo-5-chloro-4-methylane llaceta mida) · A solution of 3-chloro-4-methylaniline (5.0 g, 35.3 mmol) and pyridine (4.3 mL, 53.0 mmol) in EtOAc (35 mL) was cooled to 0 ° C, followed by the addition of acetic anhydride (5.0 mL, 53.0 mmol), and stirred at room temperature for two hours. After the addition of ethyl acetate to the reaction mixture and four washings with a 1N hydrochloric acid solution, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to produce a crude product of N-. { 3-chloro-4-methylphenyl) acetamide. The resulting crude product in acetic acid solution (35 ml) was cooled to 0 ° C, followed by the addition of a solution of bromine (3.4 ml, 67.1 mmol) in acetic acid (3.4 ml), and stirred at room temperature for 20 hours. Followed by the addition of DC to the reaction mixture, and sequential washing with a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium thiosulfate, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. It was recrystallized the resulting solid from a mixed solvent of DCM and N-hexane to yield the title compound (7.9 g, 85%, two steps) as a colorless solid. 1 H NMR (400 MHz, CDCl 3) d: 8.40 (1 H, s), 7.49 (1 H, brs), 7.39 (1 H, s), 2.31 (3 H, s), 2.23 (3 H, s).
[Example 522] Compound gg2 2-Acetamido-4-chloro-5-methylbenzoic acid A solution of A / - (2-bromo-5-chloro-4-methylphenyl) acetamide (Compound gg 1, 7.90 g, 30.1 mmol) in THF (150 mL) was cooled to -78 ° C, followed by the addition of A solution of 1 .6 M A / -butyl lithium / n-hexane (41.40 mL, 66.2 mmol) was added and stirred for 30 minutes under a nitrogen atmosphere. The reaction mixture was bubbled with carbon dioxide gas and then stirred at room temperature for 15 hours. After addition of DCM to the reaction solution which was made acidic by adding a 1 N hydrochloric acid solution, the organic layer was separated. The organic layer was concentrated under reduced pressure, and the resulting solid was washed with DCM to yield the title compound (2.55 g, 37%) as a pale brown solid.
LCMS: m / z 228 [M + H] + HPLC retention time: 1.28 min (condition of E analysis) [Example 523] Compound gg3 2-amino-4-chloro-5-methylbenzoic acid Sodium hydroxide (2.24 g, 56.0 mmol) was added to an aqueous solution (12 mL) of 2-acetamido-4-chloro-5-methylbenzoic acid (Compound gg2, 2.55 g, 11.1 mmol), and stirred for 15 hours under reflux. The reaction mixture was cooled to room temperature, and the pH of the solution was then adjusted from 4 to 5 with an aqueous solution of 35% hydrochloric acid. The precipitated solid was collected by filtration and then washed with water to yield the title compound (1.89 g, 91%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6) d: 7.63 (1 H, s), 6.83 (1 H, s), 2.17 (3 H, s).
[Example 524] Compound gg4 Ethyl 2-amino-4-chloro-5-methylbenzoate The title compound was synthesized from acid 2- amino-4-chloro-5-methylbenzoic acid (Compound gg3) under the same conditions as for Compound b1.
[Example 525] Compound gg5 Ethyl 2-amino-4-formyl-5-methylbenzoate The title compound was synthesized from ethyl 2-amino-4-chloro-5-methylbenzoate (Compound gg4) under the same conditions as for Compounds b28, b29 and b30. However, AD-mix-b was used instead of AD-mix-a.
[Example 526] Compound gg6 Ethyl 2-amino-4- (1 3-dioxolan-2-yh-5-methylbenzoate) Ethane-1,2-diol (1.73 ml, 31.1 mmol) and 4-methylbenzenesulfonic acid (18 mg, 0.62 mmol) were added to a solution of ethyl 2-amino-4-formyl-5-methylbenzoate. (Compound gg5, 1.32 g, 6.22 mmol) in toluene (62 ml), and stirred at 120 ° C for 15 hours. The reaction mixture was cooled to room temperature, and the solution was then basified by adding a saturated aqueous solution of sodium bicarbonate. The aqueous solution was extracted EtOAc, and the organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (EtOAc / n-hexane) to yield the title compound (1.25 g, 80%) as a pale brown solid.
LCMS: m / z 252 [M + H] + HPLC retention time: 1.42 min (condition of analysis E) [Example 527] Compound gg7 Ethyl 2-amino-3-chloro-4- (1 3-dioxolan-2-yl) -5-methylbenzoate The title compound was synthesized from ethyl 2-amino-4-chloro-5-methylbenzoate (Compound gg6) under the same conditions as for Compound d6.
[Example 528] Compound gg8 Ethyl 3-chloro-4-formyl-5-methylbenzoate The title compound was synthesized from ethyl 2-amino-3-chloro-4- (1, 3-dioxolan-2-yl) -5-methylbenzoate (Compound gg7) under the same conditions as for Compound b31. [Example 529] Compound gg9 3-chloro-5-methyl-4-rí (3S) -3-rmetil-r (ethyl 2-methylpropan-2-yl-oxycarbonylaminolpiperidin-1-methylmethylbenzoate) The title compound was synthesized from ethyl 3-chloro-4-formyl-5-methylbenzoate (Compound gg8) under the same conditions as for Compound b32. However, tere-butyl / V-methyl- / V - [(3S) -piperidin-3-yl] carbamate was used in place of ferric (S) -1-pyrrolidin-2-ylmethyl-carbamate. butyl, and chloroform was used instead of THF as the solvent. The reaction was carried out at a temperature of 0 ° C.
[Example 530] Compound gg10 3-chloro-5-methyl-4-rr (3S) -3-rmethyl-r (2-methylpropan-2-doxycarboninaminolpiperidin-1-methylmethyl benzoic acid Title post from 3-chloro-5- methyl-4 - [[(3S) -3- [methyl - [(2-methyl-propan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] ethyl benzoate (Compound gg9) under the same conditions as for Compound b8.
[Example 531] Compound gg1 1 A / -f (3S) -1 -rr2-chloro-4-r (5-chloro-2-ethylsulfonylphenimethylcarbamoyH-6-methylphenhydromethyl-3-in-tert-butyl methylcarbamate) The title compound was synthesized from 5-chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compound A-14. However, 3-chloro-5-methyl-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] benzoic acid was used (Compound gg 10) instead of 4-bromo-3-trifluoromethyl-benzoic acid. [Example 532] Compound GG-1 3-chloro-A / -f (5-chloro-2-ethylsulfonyl-phenylmethyl-5-methyl-4-rr (3S) -3- (methylamino) piperidin-1-methylmethylbenzamide The title compound was synthesized from N - [(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6-methylphenyl] methyl] piperidin-3-yl] A-methyl-butyl methylcarbamate (Compound gg1 1) under the same conditions as for Compound B-1.
LCMS: m / z 512 [M + H] + HPLC retention time: 0.48 min (condition of F analysis) [Example 533] Compound gg12 Ethyl 2-amino-4-methylbenzoate The title compound was synthesized from 2-amino-4-methylbenzoic acid under the same conditions as for Compound b1.
[Example 534] C t 13 The title compound was synthesized from 2-amino-4- ethyl methylbenzoate (Compound gg 12) under the same conditions as for Compound d6. However, NBS was used instead of NCS. The reaction was carried out at room temperature.
[Example 535] Compound gg14 2-fbisr (ethyl 2-methylpropan-2-ylcocarboninaminol-5-bromo-4-methylbenzoate) 4-Dimethylaminopyridine (1.224 g, 10.2 mmol) was added to a solution of ethyl 2-amino-5-bromo-4-methylbenzoate (Compound gg 13, 13.1 g, 50.8 mmol) in TH F (250 ml). ), followed by cooling to 0 ° C. Then, di-fer-butyl dicarbonate (26.6 g, 121.8 mmol) was added, and it was stirred at room temperature for 40 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (EtOAc / n-hexane) to yield the title compound (21.2 g, 91%) as a solid. colorless. 1 H-NMR (400 MHz, CDCl 3) d: 8.18 (1 H, s), 7.05 (1 H, s), 4.31 (2H, q, J = 7.2 Hz), 2.43 (3H, s), 1 .39 (18H, s), 1.35 (3H, t, J = 7.2 Hz).
[Example 536] Compound gg15 2-rbisf (2-methylpropan-2-yl) oxycarbonylminolol-5-bromo-4- (ethyl dibromomethylbenzoate) The title compound was synthesized from 2- [bis [(2-met i Ip clothing n-2-yl) oxycarbonyl] to my ethyl] -5-bromo-4-methylbenzoate (Compound gg 14) under the same conditions as for Compound b35.
[Example 537] Compound gg16 Ethyl 2-amino-5-bromo-4- (1 .3-dioxolan-2-ylbenzoate) Silver nitrate (I) (27.9 g, 164 mmol) was added to a mixed solution of 2- [bis [(2-methylpropan-2-yl) oxycarbonyl] amino] -5-bromo-4- (dibromomethyl) benzoate ethyl (Compound gg 15, 20.3 g, 32.9 mmol) in water / acetone (330 ml, 1: 2). After one hour of stirring at 65 ° C, the reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to yield a mixture of ethyl 2- [bis [(2-methylpropan-2-yl) oxycarbonyl] amino] -5-bromo-4-formylbenzoate and - [(2-methylpropan-2-yl) oxycarbonylamino] -5-bromo-4-formyl ethylbenzoate (15.4 g) as a pale yellow solid. Ethylene glycol (0.9 ml, 161 mmol) and p-toluenesulfonic acid (627 mg, 3.29 mmol) were added to a solution of the resulting crude product in toluene (330 ml), followed by stirring under reflux for 15 hours. The reaction mixture was made basic by adding a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (3.50 g, 34%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6) d: 8.03 (1 H, s), 6.93 (1 H, s), 5. 98 (1 H, s), 5.78 (2H, brs), 4.33 (2H, q, J = 7.1 Hz), 4.05-4.15 (4H, m), 1 .39 (3H, t, J = 7.1 Hz).
[Example 538] Compound gg17 Ethyl 2-amino-4- (1 .3-dioxolan-2-in-5-ethenylbenzoate) Tri- / \ - - butyl (ethenyl) tin (1.1 ml, 3.80 mmol) was added to 5 a solution of ethyl 2-amino-5-bromo-4- (1, 3-dioxolan-2-yl) benzoate (Compound gg 16, 1.00 g, 3.16 mmol), tris (dibenzylidene ketone) dipalladium (145 mg, 0.160 mmol) and tris (2-methylphenol) phosphine (97.0 mg, 0.320 mmol) in acetonitrile (32 ml), and stirred at 90 ° C for 15 hours. The reaction mixture was cooled to room temperature, and EtOAc was added. After washing with brine, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by column chromatography on silica gel (EtOAc / n-hexane) to give the title compound (615 mg, 74%) as a yellow solid.
LCMS: m / z 264 [M + H] + HPLC retention time: 1.59 min (E analysis condition) 0 [Example 539] Compound gg18 Ethyl 2-amino-4- (1,3-d-oxolan-2-yl) -5-ethylbenzoate 25 The title compound was synthesized from ethyl 2-amino-4- (1, 3-dioxolan-2-yl) -5-ethenylbenzoate (Compound gg17) under the same conditions as for Compound bb4. [Example 540] Compound gg19 Ethyl 2-amino-5-ethyl-4-formylbenzoate A mixed solution of N-methylpyrrolidone / water / sulfuric acid (18 ml, 10: 1: 1) was added to ethyl 2-amino-4- (l, 3-dioxolan-2-yl) -5-ethylbenzoate (Compound gg 18, 480 mg, 1.81 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / n-hexane) to yield the title compound (370 mg, 92%) as a yellow oily substance.
LCMS: m / z 222 [M + H] + H PLC retention time: 1.67 min (E analysis condition) [Example 541] Compound gg20 Ethyl 2-amino-3-chloro-5-ethyl-4-formylbenzoate The title compound was synthesized from ethyl 2-amino-5-ethyl-4-formylbenzoate (Compound gg19) under the same conditions as for Compound d6. However, the reaction was carried out at room temperature.
[Example 542] Compound gg21 Ethyl 3-chloro-5-ethyl-4-formylbenzoate The title compound was synthesized from ethyl 2-amino-3-chloro-5-ethyl-4-formylbenzoate (Compound gg20) under the same conditions as for Compound b31.
[Example 543] Compound gg22 3-chloro-5-ethyl-4-rr (3S) -3-rmethyl-r (ethyl 2-methylpropan-2-yl-oxycarbonyl-pyridinyl-l-methylmethylbenzoate) The title compound was synthesized from 3-chloro-5-ethyl 4-ethyl formylbenzoate (Compound gg21) under the same conditions as for Compound b32. However, ferc-butyl / V-methyl-A / - [(3S) -piperidin-3-yl] carbamate was used in place of ferric butyl (S) -1-pyrrolidin-2-ylmethyl-carbamate, and chloroform was used in place of THF as the solvent.
[Example 544] Compound gg23 3-Chloro-5-ethyl-4-rr (3S) -3- [methyl-r (2-methylpropan-2-ynyloxycarbonylamino) piperidin-1-in-methyl-benzoic acid The title compound was synthesized from 3-chloro-5-ethyl-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl ] methyl] benzoic (Compound gg22) under the same conditions as for Compound b8. [Example 545] Compound gg24 N - \ (3S) - '\ -ff2-chloro-4-f (5-chloro-2-ethylsulfonylphenimethylcarbamom-6-ethylphenimethoxypiperidin-3-yl- and v-methylcarbamate-ferric-butyl) The title compound was synthesized from hydrochloride 5-chloro-2-ethanesulfonyl-benzylamine (Compound a3) under the same conditions as for Compound A-14. However, 3-chloro-5-ethyl-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] benzoic acid was used (Compound gg23) in place of 4-bromo-3-trifluoromethyl-benzoic acid.
[Example 546] Compound GG-2 3-chloro-AM (5-chloro-2-ethylsulfonyl-phenethyl-5-ethyl-4-rf (3S) -3- (methylamino) pi pe ridin-1-methylmet liben za mida The title compound was synthesized from N - [(3S) - '[- [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6-ethylphenyl] methyl] piperidin -3-il] -A-methyl-butylcarbamate (Compound gg24) under the same conditions as for Compound B-1.
LCMS: m / z 526 [M + H] + H PLC retention time: 0.50 min (condition of F analysis [Example 547] Compound gg25 Ethyl 2-amino-5-bromo-4-formylbenzoate Silver nitrate (I) (9.7 g, 56.8 mmol) was added to a mixed solution of 2- [bis [(2-methylpropan-2-yl) oxycarbonyl] amino] -5-bromo-4- (dibromomethyl) benzoate ethyl (Compound gg 15, 7.00 g, 1 1.4 mmol) in water / acetone (12 mL, 1: 2). After one hour of stirring at 65 ° C, the reaction mixture was extracted with EtOAc. The organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to yield a mixture of ethyl 2- [bis [(2-methylpropan-2-yl) oxycarbonyl] amino] -5-bromo-4-formylbenzoate and Ethyl [(2-methylpropan-2-yl) oxycarbonylamino] -5-bromo-4-formylbenzoate (3.53 g) as a pale brown solid. A solution of 4 M hydrochloric acid / 1,4-dioxane (9.4 ml) was added to a solution of the resulting crude product in DCM (94 ml), and stirred at room temperature for 1 hour. The reaction mixture was made basic by adding a saturated aqueous solution of sodium bicarbonate, followed by extraction with EtOAc. He washed the organic layer with brine, and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting solid was recrystallized from a mixed solvent of DCM and N-hexane to yield the title compound (1.37 g, 51%, two stages) as a yellow solid.
LCMS: m / z 272 [M + H] + H PLC retention time: 1.79 min (E analysis condition) [Example 548] Compound gg26 Ethyl 2-amino-5-bromo-3-chloro-4-formylbenzoate The title compound was synthesized from ethyl 2-amino-5-bromo-4-formylbenzoate (Compound gg25) under the same conditions as for Compound d6. The reaction was carried out at room temperature.
[Example 549] Compound gg27 Ethyl 3-bromo-5-chloro-4-formylbenzoate The title compound was synthesized from ethyl 2-amino-5-bromo-3-chloro-4-formylbenzoate (Compound gg26) under the same conditions as for Compound b31.
[Example 550] Compound gg28 Ethyl 3-chloro-5-ethenyl-4-formylbenzoate The title compound was prepared from ethyl 3-bromo-5-chloro-4-formylbenzoate (Compound gg27) under the same conditions as for Compound gg17.
[Example 551] Compound gg29 Ethyl 3-chloro-5-ethenyl-4-rr (3S) -3-rmethyl-r (2-methylpropan-2-yl) oxycarbonyl-1-ylpiperidin-1-methylmethylbenzoate The title compound was synthesized from ethyl 3-chloro-5-ethenyl-4-formylbenzoate (Compound gg28) under the same conditions as for Compound b32. However, tere-butyl A / -methyl-A / - [(3S) -piperidin-3-yl] carbamate was used in place of tere-butyl (S) -1-pyrrolidin-2-ylmethyl-carbamate, and used chloroform instead of THF as a solvent.
[Example 552] Compound gg30 3-Chloro-5-ethenyl-4-rr (3S) -3-rmethyl-r (2-methyl-propan-2-yl) oxycarbonyl-1-aminolpiperidin-1 -i-P-methyl-benzoic acid The title compound was synthesized from 3-chloro-5-ethenyl-4 - [[(3S) -3- [methyl - [(2-methyl-propan-2-yl) oxycarbonyl] amino] piperidin-1-yl] ethyl] benzoate (Compound gg29) under the same conditions as for Compound b8.
[Example 553] Compound gg31 A (3S) -1-rf2-Chloro-4-rf5-chloro-2-ethylsulfon-phenylenediomethylcarbamoyl-6-ethenyl-phenyl-3-yl-a-butyl-methylcarbamate The title compound was synthesized from 5- chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compound A-14. Nevertheless, 3-Chloro-5-ethenyl-4 - [[(3S) -3- [methyl - [(2-metl-propan-2-yl) oxycarbonyl] amin or] pipe ridin-1-yl] methyl was used] benzoic (Compound gg30) instead of 4-bromo-3-trifluoromethyl-benzoic acid.
[Example 554] Compound GG-3 3-chloro - / \ / - f (5-chloro-2-ethylsulfonylphenimmetin-5-ethenyl-4-fr (3S) -3- (methylamino) piperidin-l-inmetillbenzamide The title compound was synthesized from A / - [(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6-ethenylphenyl] methyl] piperidin-3 il] -A-methyl ferba-butylcarbamate (Compound gg31) under the same conditions as for Compound B-1.
LCMS: m / z 524 [M + H] + HPLC retention time: 0.51 min (condition of F analysis) [Ex l 555] gg32 5-chloro-4-methoxyphenol) acetamide The title compound was synthesized from 3-chloro-4-methoxyaniline under the same conditions as for the Compound gg1.
[Example 556] C t gg33 tamido-4-chloro-5-methoxy benzoic The title compound was synthesized from N- (2-bromo-5-chloro-4-methoxyphenyl) acetamide (Compound gg32) under the same conditions as for Compound gg2.
[Example 557] C t gg34 no-4-chloro-5-methoxybenzoic The title compound was synthesized from 2-acetamido-4-chloro-5-methoxybenzoic acid (Compound gg33) under the same conditions as for Compound gg3.
[Example 558] Compound gg35 Ethyl 2-amino-4-chloro-5-methoxybenzoate The title compound was synthesized from 2-amino-4-chloro-5-methoxybenzoic acid (Compound gg34) under the same conditions as for Compound b1.
[Example 559] Compound gg36 Ethyl 2-amino-4-formyl-5-methoxybenzoate The title compound was synthesized from ethyl 2-amino-4-chloro-5-methoxybenzoate (Compound gg35) under the same conditions as for Compounds b28, b29 and b30.
However, under the b29 conditions, AD-mix-b was used instead of AD-mix-a.
[Example 560] Compound gg37 Ethyl 2-amino-4- (1 .3-dioxolan-2-yl) -5-methoxybenzoate The title compound was synthesized from ethyl 2-amino-4-formyl-5-methoxybenzoate (Compound gg36) under the same conditions as for Compound gg6.
[Example 561] Compound gg38 Ethyl 2-amino-4-formyl-5-methoxybenzoate The title compound was synthesized from ethyl 2-amino-4- (1, 3-dioxolan-2-yl) -5-methoxybenzoate (Compound gg37) under the same conditions as for Compound gg 19. However, the reaction was carried out at a temperature of 40 ° C. [Example 562] Compound gg39 Ethyl 2-amino-3-chloro-4-formyl-5-methoxybenzoate The title compound was synthesized from ethyl 2-amino-4-formyl-5-methoxybenzoate (Compound gg38) under the same conditions as for Compound d6.
[Example 563] Compound gg40 Ethyl 3-chloro-4-formyl-5-methoxybenzoate The title compound was synthesized from ethyl 2-amino-3-chloro-4-formyl-5-methoxybenzoate (Compound gg39) under the same conditions as for Compound b31.
[Example 564] Compound gg41 3-Chloro-5-methoxy-4-rr (3S) -3-rmethyl-r (2-methylpropan-2-yl) oxycarbonylamino] piperidin-1-methylmethylbenzoate ethyl The title compound was synthesized from ethyl 3-chloro-4-formyl-5-methoxybenzoate (Compound gg40) under the same conditions as for Compound b32. However, ferc-butyl / V-methyl-A / - [(3S) -piperidin-3-yl] carbamate was used in place of ferric butyl (S) -1-pyrrolidin-2-ylmethyl-carbamate, and chloroform was used instead of TH F as the solvent.
[Example 565] Compound gg42 3-Chloro-5-methoxy-4-fr (3S) -3-fmethyl-r (2-methylpropan-2-yl) oxycarboninaminolpiperidin-1-i H methyl P benzoic acid The title compound was synthesized from 3-chloro-5-methoxy-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1 -i I] meti I] benzoate (Compound gg41) under the same conditions as for Compound b8.
[Example 566] Compound gg43 / \ / - f (3S) -1-f [2-chloro-4-f (5-chloro-2-ethylsulfonyl-phenylmethylcarbamoyl-6-methoxypheninmethylpiperidin-3-yl1 - / tert-butyl methylcarbamate) The title compound was synthesized from 5- chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compound A-14. However, 3-chloro-5-methoxy-4 - [[(3S) -3- [methyl - [(2-methyl-propan-2-yl) oxycarbonyl] amino] piperidin-1-i I] m et was used. i I] benzoic acid (Compound gg42) in place of 4-bromo-3-trifluoromethyl-benzoic acid, and DCM was used in place of DM F as the solvent.
[Example 567] Compound GG-4 3-chloro-A / - | (5-Chloro-2-ethylsulfonylphenimethi-N-5-methoxy-4-fr (3Sl-3- (methylamino) piperidin-l-methylmethylbenzamide The title compound was synthesized from A / - [(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6-methoxyphenyl] methyl] piperidin-3 il] - / \ / - ferric butyl methylcarbamate (Compound gg43) under the same conditions as for Compound B-1.
LCMS: m / z 528 [M + H] + HPLC retention time: 0.41 min (condition of F analysis) [Example 568] Compound gg44 3-Chloro-5-methoxy-4-fr4-r (2-methylpropan-2-ynyloxycarbonylpiperazin-1-p-benzoic acid) The title compound was synthesized from ethyl 3-chloro-4-formyl-5-methoxybenzoate (Compound gg40) under the same conditions as for Compounds gg41 and gg42. Without However, under the conditions of gg41, piperzine-1-butch-butyl carboxylate was used instead of A / -methyl- / V - [(3S) -piperidin-3-yl-butyl ylcarbamate.
[Example 569] Compound GG-5 3-chloro- / V-f (5-chloro-2-ethylsulfonylphenyl) metin-5-methoxy-4- (piperazin-1-methylmethylbenzamide) The title compound was synthesized from 5-chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compounds gg43 and GG-4. However, under the conditions of gg43, 3-chloro-5-methoxy-4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-ylmethylbenzoic acid (Compound gg44) was used instead of 3-chloro-5-methoxy-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) ox i carbonyl] amino] piperidin-1-ylmethylbenzoic acid (Compound 9942).
LCMS: m / z 500 [M + H] + HPLC retention time: 0.44 min (condition of F analysis) [Example 570] Compound GG-6 3-chloro- / V-r (5-chloro-2-ethylsulfonylphennin-5-methoxy-4-r (4-methyl-piperazin-1-di-methyl-benzamide) The title compound was synthesized from 3-chloro- / N / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5-methoxy-4- (piperazin-1-methylmethyl) benzamide (Compound GG-5) under the same conditions as for Compound B-2.
LCMS: m / z 514 [M + H] + HPLC retention time: 0.47 min (condition of F analysis) [Example 571] Compound K-1 N-f (5-chloro-2-ethylsulfonylphenyl) methyH-3-cyano-4-rf (3S) -3- (methylamino) piperidin-1-iHmethyl-5- (trifluoromethylbenzamide) Copper cyanide (1) (12.9 mg, 0.144 mmol) was added to a solution of (S) -3-bromo-A / - (5-chloro-2- (ethylsulfonyl) benzyl) -4 - ((3- ( methylamino) piperidin-1-yl) methyl) -5- (trifluoromethyl) benzamide (Compound E-8, 73.1 mg, 0.120 mmol) in DM F (1.0 mi) a room temperature, and stirred at 130 ° C to 150 ° C under microwave irradiation for 30 minutes. After cooling to room temperature, ethyl acetate was added to the reaction mixture, and the organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate, water and brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH / DCM) to yield the title compound (39.7 mg, 60%) as a colorless foamy substance.
LCMS: m / z 557 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 572] Compound K-2 N-r (5-Chloro-2-ethylsulfonyl-phenylmethyl-3-methoxy-4-rf (3S) -3- (methylamino) piperidin-1-ylmethin-5- (trifluoromethylbenzam ida) Sodium methoxide (41.5 mg, 0.768 mmol) was added to a solution of (S) -3-bromo- / V- (5-chloro-2- (ethylsulfonyl) benzyl) -4 - ((3- (methylamino) ) piperidin-1-yl) methyl) -5- (trifluoromethyl) benzamide (Compound E-8, 104 mg, 0.171 mmol) in MeOH (16 mL) at room temperature, and stirred for 30 minutes at 1 10 ° C at 130 ° C under microwave irradiation. After cooling to room temperature, ethyl acetate was added to the reaction mixture, and the organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by preparative HPLC (water / acetonitrile, 0.05% TFA) to yield the title compound (84.4 mg, 88%) as a colorless foamy substance.
LCMS: m / z 562 [M + H] + HPLC retention time: 0.43 min (analysis condition A) [Example 573] Compound K-3 N-r (5-Chloro-2-ethylsulfonylphenylmethyl-3-cyano-4- (piperazin-1-methylmethin-5- (trifluoromethylbenzene) The title compound was synthesized from 3-bromo-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide (Compound EE-1) under the same conditions as for Compound K-1.
LCMS: m / z 529 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 574] Compound K-4 N-r (5-chloro-2-ethylsulfonylphenyl) metin-3-methoxy-4- (DiDerazin-1-methylmethyl) -5- (trifluoromethylbenzamide The title compound was synthesized from 3-bromo-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide (Compound EE-1) under the same conditions as for Compound K-2. However, the reaction was carried out with the addition of copper iodide.
LCMS: m / z 534 [M + H] + HPLC retention time: 0.47 min (analysis condition A) [Example 575] Compound K-5 N-rf5-chloro-2-ethylsulfonylphenyl) metin-3-cyano-4 - [(4-methyl-piperazin-1-inmethyl-5- (trifluoromethyl-benzamide The title compound was synthesized from 3-bromo- / V- [(5-chloro-2-ethylsulfonylphenyl) methyl] -4 - [(4-methylpiperazin-1 -i I) methyl I] -5- (trifluoromethyl) ) benzamide (Compound EE-2) under the same conditions as for Compound K-1.
LCMS: m / z 543 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 576] Compound K-6 N-R (5-chloro-2-ethylsulfonylphenyl) methyH-3-methoxy-4-f (4-methylpiperazin-1-yl) methyl-1-5- (trifluoromethyl) benzamide The title compound was synthesized from 3-bromo-N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4 - [(4-methylpiperazin-1-yl) methyl] -5- (trifluoromethyl) benzamide ( Compound EE-2) under the same conditions as for Compound K-2. However, the reaction was carried out with the addition of copper iodide.
LCMS: m / z 548 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 577] Compound K-7 -3-aminopyrrolidin-1 -inmetill-V-r (5-chloro-2- Ethylsulfonylphenyl) methion-3-methoxy-5- (trifluoromethyl-P-benzamide The title compound was synthesized from 4 - [[(3R) -3-aminopyrrolidin-1-yl] methyl] -3-bromo-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] - 5- (trifluoromethyl) benzamide (Compound E-2) under the same conditions as for Compound K-2. However, the reaction was carried out with the addition of copper iodide.
LCMS: m / z 534 [M + H] + HPLC retention time: 1.08 min (analysis condition D) [Example 578] Compound k1 Ethyl 2-amino-4-formyl-3-methyl-5- (trifluoromethyl) benzoate Potassium trifluoro (methyl) borate (430 mg, 3.53 mmol), butyldi-1-adamylphosphine (63.3 mg) was added., 0.176 mmol), potassium carbonate (731 mg, 5.29 mmol) and palladium acetate (11) (19.8 mg, 0.0880 mmol) to a mixed solution of 2-amino-3-bromo-4-formyl-5- (trifluoromethyl). ethyl benzoate (Compound e1, 600 mg, 1.76 mmol) in toluene (6.0 ml) and water (2.0 ml) at room temperature, and stirred at 90 ° C for 15 hours. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (203 mg, 42%) as a pale yellow solid.
LCMS: m / z 276 [M + H] + HPLC retention time: 0.87 min (analysis condition A) [Example 579] Compound k2 Ethyl 4-formyl-3-methyl-5- (trifluoromethyl) benzoate The title compound was synthesized from ethyl 2-amino-4-formyl-3-methyl-5- (trifluoromethyl) benzoate (Compound k1) under the same conditions as for Compound b31. [Example 580] Compound k3 4-Formyl-3-methyl-5- (trifluoromethyl) benzoic acid The title compound was synthesized from ethyl 4-formyl-3-methyl-5- (trifluoromethyl) benzoate (Compound k2) under the same conditions as for Compound b8.
[Example 581] Compound k4 N-r (5-chloro-2-ethylsulfonylphenyl) methyN-4-formyl-3-methyl-5- (trifluoromethylbenzamide) The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, 4-fo rm i l-3-methyl-5- (triflu or romethyl) benzoic acid was used (Compound k3) instead of 4 - [[4 - [(2-methylpropan-2- il) oxycarbonyl] piperazin-1 -i l] met i l] -3- (trifluoromethyl) benzoic acid (Compound b3).
[Example 582] Compound k5 A / -r (3S) -1 -ff4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamom-2-methyl-6- (trifluoromethyl) phenylmethylpperidin-3-iH-A / tert-methylcarbamate butyl The title compound was synthesized from A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-3-methyl-5- (trifluoromethyl) benzamide (Compound k4) under the same conditions as for the Compound b32. However, / V-methyl - / \ / - [(3S) -piperidin-3-ylcarbamic acid-butyl ester was used instead of (S) -1-pyrrolidin-2-yl-butylcarbamate-butyl ester, and was used chloroform instead of THF as a solvent.
[Example 583] Compound K-8 N-f (5-chloro-2-ethylsulfonylphenyl) methylene-3-methyl-4-rf (3S) -3- The title compound was synthesized from A / - [(3S) -1 - [[4- [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -2-methyl-6- (trifluoromethyl) phenyl] methyl] piperidin -3-yl] - / \ / - tert-butyl methylcarbamate (Compound k5) under the same conditions as for Compound B-57.
LCMS: m / z 546 [M + H] + HPLC retention time: 0.54 min (condition of analysis A) [Example 584] Compound K-9 IM-α (5-chloro-2-ethylsulfonylphenyl) metiN-3-methyl-4- (piperazin-1-ylmethi-5- (trifluoromethyl-P-benzamide The title compound was synthesized from / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-3-methyl-5- (trifluoromethyl) benzamide (Compound k4) under the same conditions as for the Compounds k5 and K-8. However, piperazine-1-fer-butyl carboxylate was used instead of A / -methyl-butyl-A / - [(3S) -piperidin-3-yl] carbamate under the conditions for Compound k5.
LCMS: m / z 518 [M + H] + HPLC retention time: 0.52 min (condition of Analysis A) [Example 585] Compound K-10 N-r (5-chloro-2-ethyl) -3-methyl-4-r (4-methyloioerazin-1-inmethyl-1-5- (trifluoromethyl-D-benzamide title post from N - [(5-chloro-2-ethylsulfonylphenyl) methyl] -3-methyl-4- (piperazin-1 -i Imeti I) -5- (trifluoromethyl) benzamide (Compound K-9) under the same conditions as for Compound B-2.
LCMS: m / z 532 [M + H] + HPLC retention time: 0.52 min (analysis condition A) [Example 586] Compound k6 3-bromo-4- [r (3S) -3- [methyl-r (ethyl 2-methyl-propan-2-yl-oxo-carbonylaminolpiperidin-l -inmetin-5- (trifluoromethyl) benzoate] The title compound was synthesized from ethyl 3-bromo-4-formyl-5- (trifluoromethyl) benzoate (Compound e2) under the same conditions as for Compound b32. However, A / -methyl-A / - [(3S) -piperidin-3-yl] -er-butyl ester carbamate was used in place of ferric butyl (S) -1-pyrrolidin-2-ylmethyl-carbamate, and chloroform was used in place of THF as the solvent.
[Example 587] Compound k7 3-ethenyl-4-rf (3S) -3-rmethyl-f (ethyl 2-methyl-propane-2-yl-oxycarbonylaminolpiperidin-1-immethyl-5- (trifluoromethylbenzoate The title compound was synthesized from 3-bromo-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5- (trifluoromethyl) benzoate of ethyl (Compound k6) under the same conditions as for Compound k1. However, potassium trifluoro (vinyl) borate was used in place of potassium trifluoro (methyl) borate.
[Example 588] Compound k8 3-ethenyl-4-rr (3S) -3-fmethyl-f (2-methylpropan-2-yl) oxycarboninaminolpiperidin-1-iHmetM1-5- (trifluoromethyl) benzoic acid tethyzed the title compound from 3-ethenyl-4- [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-y!] methyl] -5 - (ethyl trifluoromethyl) benzoate (Compound k7) under the same conditions as for Compound b8.
[Example 589] Compound k9 / V-f (3S) -1-rf4-f (5-Chloro-2-ethylsulfonyl-phenylmethylcarbamoyl-2-ethenyl-6- (trifluoromethylpheniHmethylpiperidin-3-in / tere-butyl-V-methylcarbamate) The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, 3-ethenyl-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5- (trifluoromethyl) acid was used. ) benzoic acid (Compound k8) instead of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3).
[Example 590] Compound K-1 1 N-R (5-Chloro-2-ethylsulfonylphenimethyl-3-ethenyl-4-rr (3S) -3- (methylamino) piperidin-1-methylmethyl-5- (trifluoromethylbenzamide) The title compound was synthesized from N - [(3S) -1 - [[4- [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -2-ethenyl-6- (tri fl uo rom et i I) nyl] methyl] piperidin-3-yl] - / S / -methoxy tert-butyl ester (Compound k9) under the same conditions as for Compound B-57.
LCMS: m / z 558 [M + H] HPLC retention time: 0.56 min (analysis condition A) [Example 591] Compound k10 3-ethyl-3-rmethyl-f (2-methylpropan-2- il) oxycarbonylaminolpiperidin-1 -illmetin-5- (ethyl trifluoromethylbenzoate) The title compound was synthesized from 3-ethenyl-4- [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5 - (ethyl trifluoromethyl) benzoate (Compound k7) under the same conditions as for Compound bb4. However, ethyl acetate was used in place of methanol as the solvent.
[Example 592] Compound K-12 N-r (5-Chloro-2-ethylsulfonylphenimethoxy) -3-ethyl-4-rr (3S) -3- (methylamino) piperidin-1-inmetin-5- (trifluoromethyl) benzamide fifteen The title compound was synthesized from 3-ethyl-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5 - (ethyl trifluoromethyl) benzoate (Compound k10) under the same conditions as for Compounds k8, k9 and K-1 1. 20 LCMS: m / z 560 [M + H] HPLC retention time: 0.56 min (analysis condition A) [Example 593] Compound k 11 25 2-amino-3-cyclopropyl-4-formyl-5- (ethyl trifluoromethylbenzoate The title compound was synthesized from ethyl 2-amino-3-bromo-4-formyl-5- (trifluoromethyl) benzoate (Compound e1) under the same conditions as for Compound k1. However, potassium cyclopropyltrifluoroborate was used in place of potassium trifluoro (methyl) borate.
[Example 594] Compound k12 N-f (5-chloro-2-ethylsulfonylphenyl) methyl-3-cyclopropyl-4-formyl-5- (trifluoromethyl) benzamide The title compound was synthesized from ethyl 2-amino-3-cyclopropyl-4-formyl-5- (trifluoromethyl) benzoate (Compound k 1 1) under the same conditions as for Compounds k2, k3 and k4.
[Example 595] Compound k13 4- f (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-2-cyclopropyl-6- (trifluoromethyl) pheninmethylpiperazine-l-tere-butylcarboxylate The title compound was synthesized from / V - [(5-chloro-2-ethylsulfonyl-phenyl) -methyl] -3-cyclopropyl-4-formyl-5- (trifluoromethyl) -benzamide (Compound k12) under the same conditions as for the Compound b32. However, piperazine-1-fer-butylcarboxylate was used in place of ferricbutyl (S) -1-pyrrolidin-2-ylmethylcarbamate, and chloroform was used in place of THF as the solvent.
[Example 596] Compound K-13 N-f (5-Chloro-2-ethylsulfonylphenimethyl) -1-3-cyclopropyl-4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide The title compound was synthesized from 4 - [[4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -2-cyclopropyl-6- (trifluoromethyl) phenyl] methyl] piperazine-1-carboxylic acid ferric acid. butyl (Compound k 13) under the same conditions as for Compound B-1.
LCMS: m / z 544 [M + H] HPLC retention time: 0.58 min (analysis condition A) [Example 597] Compound K-14 N-R (5-chloro-2-ethylsulfonylphenyl) methyH-3-cyclopropyl-4-r (4-methylpiperazin-1-yl) metin-5- (trifluoromethylbenzamide The title compound was synthesized from A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -3-cyclopropyl-4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide (Compound K-13 ) under the same conditions as for Compound B-2.
LCMS: m / z 558 [M + H] HPLC retention time: 0.56 min (analysis condition A) [Example 598] Compound K-15 N-f (5-chloro-2-ethylsulfonylphenyl) methyl-3-cyclopropyl-4-fr (3S) -3- (methylamino) piperidin-l -nmetH-5- (trifluoromethylbenzamide) The title compound was synthesized from A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -3-cyclopropyl-4-formyl-5- (trifluoromethyl) benzamide (Compound k12) under the same conditions as for the Compounds k13 and K-13. However, under Compound k13 conditions, / V-methyl-A / - [(3S) -piperidin-3-yl] carbamate was used (ere-butyl instead of piperazine-1-ferro-butyl carboxylate.
LCMS: m / z 572 [M + H] + H PLC retention time: 0.61 min (analysis condition A) [Example 599] Compound 11 4-Hydroxy-3- (trifluoromethyl) benzoic acid Pyridine hydrochloride (262 mg, 2.27 mmol) was added to 4-methoxy-3- (trifluoromethyl) benzoic acid (50.0 mg, 0.227 mmol), and heated at 160 ° C for eight hours. The reaction mixture was cooled to room temperature, and then an aqueous solution of 10% citric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. HE purify the resulting residue by silica gel column chromatography (methanol / dichloromethane) to give the title compound (46.0 mg, 98%) as a colorless solid.
LCMS: m / z 205 [M-H] - HPLC retention time: 0.52 min (condition of F analysis) [Example 600] Compound L-1 f2-chloro-4-f (5-chloro-2-ethylsulfonylphenimethylcarbamoyH-6- (trifluoromethylphenyl) acetate Sulfuryl chloride (54.0 ml, 0.670 mmol) was added to a solution of 4-hydroxy-3- (trifluoromethyl) benzoic acid (Compound 11, 46.0 mg, 0.223 mmol) in acetic acid (1 ml), and stirred at 60 ° C for 16 hours. The reaction mixture was cooled to room temperature, followed by the addition of water and extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride twice, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was dissolved in DCM (2.2 ml), to which 5-chloro-2- hydrochloride was added. ethanesulfonyl-benzylamine (Compound a3, 75.0 mg, 0.278 mmol), DIPEA (0.106 ml, 0.642 mmol) and HBTU (97.0 mg, 0.257 mmol) while cooling to 0 ° C in an ice water bath, and the mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (26.0 mg, 23%) as a yellow solid.
LCMS: m / z 498 [M + H] + HPLC retention time: 0.88 min (condition of F analysis) [Example 601] Compound I2 N-f (5-chloro-2-ethylsulfonylphenyl) methyH-4-hydroxy-3- (trifluoromethyl) benzamide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the Same conditions as for Compound A-21. However, 4-hydroxy-3- (trifluoromethyl) benzoic acid (Compound 11) was used in place of 3- (trifluoromethyl) benzoic acid.
[Example 602] Compound I3 4-r4-f (5-chloro-2-ethylsulfonylphenimethylcarbamoyl-2- (trifluoromethyl) phenoxylpiperidine-1-carboxylic acid fer-butyl ester 4-Hydroxypiperidine-1-carboxylic acid fer-t-butylester (21.5 mg, 0.107 mmol), diisopropyl azodicarboxylate (21.0 mI, 0.107 mmol) and triphenylphosphine (28.0 mg, 0.107 mmol) were added to a solution of / S / - [(5-Chloro-2-ethylsulfonylphenyl) methyl] -4-hydroxy-3- (trifluoromethyl) benzamide (Compound I2, 30.0 mg, 0.071 mmol) in THF (1 mL), and the mixture was stirred at room temperature ambient. After one hour, 4-hydroxypiperidine-1-carboxylic acid terebutyl ester (21.5 mg, 0.107 mmol), diisopropyl azodicarboxylate (21.0 m 1, 0.107 mmol) and triphenylphosphine (28.0 mg, 0.107 mmol) were added. they added further, and the mixture was stirred at 50 ° C for 18 hours. The reaction mixture was cooled to room temperature, followed by the addition of water and extraction with ethyl acetate. He washed organic layer with brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (43.0 mg, quant.) As a colorless oily substance.
LCMS: m / z 605 [M + H] + HPLC retention time: 0.97 min (condition of F analysis) [Example 603] Compound L-2 N-f (5-chloro-2-ethylsulfonylphenimethyl-4-pperidin-4-yloxy-3- (trifluoromethylbenzamide The title compound was synthesized from 4- [4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -2- (trifluoromethyl) phenoxy] piperidine-1-carboxylic acid (tert-butyl) ester (Compound I3) under the same conditions as for Compound B-1.
LCMS: m / z 505 [M + H] + HPLC retention time: 0.52 min (condition of F analysis) [Example 604] Compound L-3 N-f (5-Chloro-2-ethylsulfonylphenimetin-4-ff3R1-piperidin-3-ylloxy-3- (trifluoromethylbenzamide The title compound was synthesized from A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-hydroxy-3- (trifluoromethyl) benzamide (Compound 12) under the same conditions as for Compounds 13 and L -2. However, under the conditions of Compound 13, (3S) -3-hydroxypiperidine-1-fer-butylcarboxylate was used in place of 4-hydroxypiperidine-1-tert-butylcarboxylate.
LCMS: m / z 505 [M + H] + H PLC retention time: 0.51 min (analysis condition F) [Example 605] Compound m1 5-Vodo-3- (trifluoromethyl) pyridin-2-amine A solution of 3- (trifluoromethyl) pyridin-2-amine (1.50 g, 9.25 mmol) in acetic acid (15 mL) was cooled to 0 ° C, followed by addition of N IS (2.08 g, 9.25 mmol), and warmed to room temperature and stirred for 20 hours. NIS (1.04 g, 4.62 mmol) was then further added at room temperature, and the mixture was stirred for 70 hours. Water was added to the reaction mixture, and the precipitate was filtered and then washed with an aqueous solution of 5% sodium thiosulfate, an aqueous solution of 10% sodium bicarbonate, and water to produce the title compound ( 2.36 g, 89%) as a colorless solid.
LCMS: m / z 289 [M + H] + H PLC retention time: 0.70 min (analysis condition A) [Example 606] Composite m2 6-amino-5- (trifluoromethylpyridine-3-carbonitrile) Copper cyanide (1) (805 mg, 8.99 mmol) was added to a solution of 5-iodo-3- (trifluoromethyl) pyridin-2-amine (Compound m1, 1.29 g, 4.49 mmol) in DMF (13 ml. ), and stirred at 130 to 150 ° C for four hours. The mixture was cooled to room temperature, followed by removal of the insoluble matter by filtration through celite, and washed with ethyl acetate. A saturated aqueous solution of sodium bicarbonate was added to the filtrate, followed by extraction. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (840 mg, quant.) As a pale brown solid.
LC S: m / z 188 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 607] Compound m3 6-amino-5- (methyl trifluoromethylpyridine-3-carboxylate) Sulfuric acid (1 mL) was added to a solution of 6-amino-5- (trifluoromethyl) pyridine-3-carbonitrile (Compound m2, 840 mg, 4.49 mmol) in MeOH (10 mL) at room temperature, and heated to room temperature. 140 to 150 ° C and stirred for 30 minutes by microwaves. The reaction mixture was then cooled to room temperature, neutralized with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate was added thereto. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (483 mg, 49%) as a pale yellow solid.
LCMS: m / z 221 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 608] Compound m4 Á id 6 i o-5- (trifluoromethyl) pyridine-3-carboxylic acid The title compound was synthesized from methyl 6-amino-5- (trifluoromethyl) pyridine-3-carboxylate (Compound m3) under the same conditions as for Compound b8.
[Example 609] Compound M-1 6-amino-A / -r (5-chloro-2-ethylsulfonylphenyl) methyH-5- (trifluoromethyl) pyridine-3-carboxamide omitted title from hydrochloride (5-chloro-2-ethylsulfonylphenyl) methanamine (Compound a3) under the same conditions as for Compound bb10. However, 6-amino-5- (trifluoromethyl) pyridine-3-carboxylic acid (Compound m4) was used in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazine-1-acid. i I] methyl] -3- (triflu or romethyl) benzoic (Compound b3).
LCMS: m / z 422 [M + H] + HPLC retention time: 0.64 min (analysis condition A) [Example 610] Compound M-2 N-R (5-chloro-2-ethylsulfonylphenyl) metin-2-methyl-5- (trifluoromethyl) -1 .3-oxazole-4-carboxamide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound A-5. However, 2-methyl-5- (trifluoromethyl) -1,3-oxazole-4-carboxylic acid was used in place of 3- (trifluoromethyl) benzoic acid.
LCMS: m / z 41 1 [M + H] + HPLC retention time: 0.81 min (analysis condition A) [Example 61 1] Compound N- 1 N-r (5-Chloro-2-ethylsulfonyl) -lfyninmethyl-6- (trifluoromethyl) pyridine-2-carboxamide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, 6- (trifluoromethyl) pyridine-2-carboxylic acid was used in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- ( trifluoromethyl) benzoic acid (Compound b3).
LCMS: m / z 407 [M + H] + HPLC retention time: 0.78 min (analysis condition A) [Example 612] Compound N- 2 N-r (5-chloro-2-ethylsulfonylphenyl) metin-2- (trifluoromethyl) pyridine-4-carboxamide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, 2- (trifluoromethyl) pyridine-4-carboxylic acid was used in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- acid. (trifluoromethyl) benzoic acid (Compound b3).
LCMS: m / z 407 [M + H] + HPLC retention time: 0.73 min (analysis condition A) what [Example 613] Compound N- 3 N-r (5-Chloro-2-ethylsulfonyl-phenylmethyl-4- (trifluoromethylpyridine-2-carboxamide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, 4- (trifluoromethyl) pyridine-2-carboxylic acid was used in place of 4- [[4- [(2-methyl p-n-2-yl) oxica] rbonyl] pipera zin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3).
LCMS: m / z 407 [M + H] + 25 HPLC retention time: 0.81 min (condition of Analysis A) [Example 614] Compound N- 4 N-r (5-chloro-2-ethylsulfonylphenyl) methyl-1-phenyl-5-pyrrol-1-ylpyrazole-4-carboxamide The title compound was synthesized from hydrochloride (5-chloro-2-ethylsulfonylphenyl) methanamine (Compound a3) under the same conditions as for Compound A-21. However, 1-phenyl-5-pyrrol-1-ylpyrazole-4-carboxylic acid was used in place of 3- (trifluoromethyl) benzoic acid, and DM F was used in place of dichloromethane as the solvent.
LCMS: m / z 469 [M + H] + HPLC retention time: 0.83 min (condition of F analysis) [Example 615] Compound N- 5 N-f (5-chloro-2-ethylsulfonylphenol) metin-3,5-bis (trifluoromethylbenzamide) The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound A-21. However, 3,5-bis (trifluoromethyl) benzoic acid was used in place of 3- (trifluoromethyl) benzoic acid.
LCMS: m / z 474 [M + H] + H PLC retention time: 0.93 min (analysis condition F) [Example 616] Compound N- 6 4-amino-A / -f (5-chloro-2-ethylsulfonyl-phenylmethyl-3- (trifluoromethyl-P-benzamide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound A-21. However, 4-amino-3- (trifluoromethyl) benzoic acid was used in place of 3- (trifluoromethyl) benzoic acid.
LCMS: m / z 421 [M + H] + HPLC retention time: 0.73 min (condition of F analysis) [Example 617] Compound h 1 2-ethylsulfanyl-5- (trifluoromethyl) aniline synthesized the title compound from 2-amino-4- (trifluoromethyl) benzenethiol hydrochloride under the same conditions as for Compound a4.
[Example 618] Compound n2 r2-Ethylsulfanyl-5- (trifluoromethyl) phenyNhydrazine The title compound was synthesized from 2-ethylsulfanil 5- (trifluoromethyl) aniline (Compound n 1) under the same conditions as for Compound a5.
[Example 619] Compound n3 3-chloro-N'-r2-ethylsulfanyl-5- (trifluoromethyl-phenyl) -5- (trifluoromethylbenzohydrazide The title compound was synthesized from [-eti Isulfa n il- 5- (trifluoromethyl) phenyl] hydrazine (Compound n2) under the same conditions as for Compound A-1. However, 3-chloro-5- (trifluoromethyl) benzoic acid was used in place of 3-bromo-5- (trifluoromethyl) benzoic acid.
[Example 620] Compound h / -7 3-chloro-N, -r2-ethylsulfonyl-5- (trifluoromethylphenyl-5- (trifluoromethyl) benzohydrazide The title compound was synthesized from 3-chloro-N '- [2-ethylsulfanyl-5- (trifluoromethyl) phenyl] -5- (trifluoromethyl) benzohydrazide (Compound n3) under the same conditions as for the Compound A-2.
LCMS: m / z 475 [M + H] + HPLC retention time: 0.97 min (condition of F analysis) [Example 621] Compound n4 -2-methyl-1,3-benzothiazole The title compound was synthesized from 2-methyl-1,3-benzothiazol-5-ol under the same conditions as for Compound a4.
[Example 622] Compound n5 2-amino-4-ethoxybenzenethiol An aqueous solution of sodium hydroxide at 30% by weight (13 ml) and ethylene glycol (13 ml) was added to 5-ethoxy-2-methyl-1,3-benzothiazole (Compound n4, 858 mg, 4.44 mmol) at room temperature under a nitrogen atmosphere, and the reaction suspension mixture was stirred under reflux for 5.5 hours. After cooling to room temperature, the organic layer was washed with diethyl ether three times (20 ml x 3); and the aqueous layer was cooled to 0 ° C, then adjusted to pH 2 or 3 by adding an aqueous solution of 36% hydrochloric acid, and extracted with diethyl ether. The combined organic layers were sequentially washed with brine and water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to yield the title compound as a crude product. 1 H-NMR (400 MHz, DMSO-d 6) d: 7.28 (1 H, d, J = 7.9 Hz), 6.24-6.29 (2H, m), 4.29 (2H, brs), 3.97 (2H, q, J = 6.9 Hz), 2.76 (1 H, s), 1 .38 (3H, t, J = 6.9 Hz).
[Example 623] Compound N- 8 3-Chloro-N '- (5-ethoxy-2-ethylsulfonylphenih-5- (trifluoromethyl) benzohydrazide The title compound was synthesized from 2-amino-4-ethoxybenzenethiol (Compound n5) under the same conditions as for Compounds n1, n2, n3 and N-7.
LCMS: m / z 451 [M + H] + HPLC retention time: 0.93 min (condition of F analysis) [Example 624] Compound n6 / \ M (3R) -1 -rr4-r (3,5-dichloro-2-ethylsulfonylphenyl) methylcarbamoyH-2- (trifluoromethyl-1Heninmethylpyrrolidin-3-in-A / tert-butyl methylcarbamate) The title compound was synthesized from (3,5-dichloro-2 ethylsulfonylphenyl) methanamine (Compound bb9) under the same conditions as for Compound bb10. However, 4 - [[(3R) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] pyrrolidin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b) was used. 1 1) in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3).
[Example 625] Compound N- 9 N-r (3,5-dichloro-2-ethylsulfonylphenimetin-4-rr (3R) -3- (methylamino) pyrrolidin-l-inmetill-3- (trifluoromethylbenzamide The title compound was synthesized from A / - [(3R) -1 - [[4- [(3,5-dichloro-2-ethylsulfonylphenol) methylcarbamoyl] -2- (trifluoromethyl) phenyl] methyl] pyrrolidine -3-yl] - / N- / tert-butylmethylcarbamate (Compound n6) under the same conditions as for Compound B-57.
LCMS: m / z 552 [M + H] + HPLC retention time: 0.49 min (analysis condition A) [Example 626] Compound n7 -6-methylaniline N IS (2.95 g, 13.1 mmol) was added to a solution of 4-chloro-2-methylaniline (1.69 g, 12.0 mmol) in DMF (27 mL), and stirred at room temperature for 1.5 hours under an atmosphere of nitrogen. N IS (738 mg, 3.28 mmol) was added, followed by another 1.5 hours of stirring. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed with a saturated aqueous solution of sodium thiosulfate, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.51 g, 47%) as a pale brown solid.
LCMS: m / z 268 [M + H] + HPLC retention time: 2.68 min (analysis condition D) [Example 627] Compound n8 2-amino-5-chloro-3-methylbenzonitrile intetized the title compound from 4-chloro-2- and tilaniline (Compound n7) under the same conditions as for Compound dd48. However, the reaction was carried out at a temperature of 140 to 150 ° C.
[Example 628] Compound n9 5 l 2 vodo-3-methylbenzonitrile intetized the title compound from 2-amino-5- ethylbenzonitrile (Compound n8) under the same conditions as for Compound dd49.
[Example 629] Compound n 10 5-chloro-2-ethylsulfanyl-3-methylbenzonitrile intetizó the title compound from 5-chloro-2-tilbenzonitrilo (Compound n9) under the same it's like for Compound dd42. However, it performed the reaction at a temperature of 80 ° C.
[Example 630] Compound n 1 1 2,2-trifluoroacetate (5-chloro-2-ethylsulfanyl-3-methylphenimmethanamine) A solution of 5-chloro-2-ethylsulfanyl-3-methylbenzonitrile (Compound n 10, 95.4 mg, 0.450 mmol) in THF (2 mL) was added to a solution of lithium aluminum hydride (27.5 mg, 0.579 mmol) in THF (4.5 mL) was cooled under ice, and warmed to room temperature and stirred for five hours under a nitrogen atmosphere. Lithium aluminum hydride (35.8 mg, 0.754 mmol) was further added under cooling with ice, and the mixture was warmed to room temperature and stirred for 2.5 hours under a nitrogen atmosphere. Water (25 μl), a 5N sodium hydroxide solution (25 ml), THF (600 μl) and water (60 ml) were added to the reaction suspension under ice cooling, followed by 30 minutes of stirring and removal. of the insoluble matter by filtration through celite, and washed with THF. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (water / acetonitrile, 0.05% TFA) to yield the title compound (69.3 mg, 47%) as a colorless solid.
LCMS: m / z 216 [M + H] + HPLC retention time: 0.44 min (condition of F analysis) [Example 631] Compound n 12 (5-Chloro-2-ethylsulfonyl-3-methylphenyl) methanamine hydrochloride The title compound was synthesized from 2,2-trifluoroacetate of (5-chloro-2-ethylsulfanyl-3-methylphenyl) methanamine (Compound n 1 1) under the same conditions as for Compound dd45.
[Example 632] Compound N- 10 N-f (5-Chloro-2-ethylsulfonyl-3-methylphenithmetyl-4-r [(3SL-3- (methylamino) piperidin-1-methylmethyl-3- (trifluoromethyl) benzamide The title compound was synthesized from (5-chloro-2-ethylsulfonyl-3-methylphenyl) methanamine hydrochloride (Compound n12) under the same conditions as for Compounds n6 and N-9.
However, 4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b17) instead of 4 - [[(3R) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] pyrrolidin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b1 1) under the conditions for Compound n6.
LCMS: m / z 546 [M + H] + HPLC retention time: 0.56 min (condition of F analysis) [Example 633] Compound N-1 1 3-chloro-A / -r (5-chloro-2-ethylsulphonyl-3-methylphenylmethyl-4-fr (3S) -3- (methylamino) piperidin-1-methylmethyl-5- (trifluoromethylbenzamide The title compound was synthesized from (5-chloro-2-ethylsulfonyl-3-methylphenyl) methanamine hydrochloride (Compound n12) under the same conditions as for Compounds n6 and N-9. However, under the conditions of Compound n6, 3-chloro-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] acid was used] methyl] -5- (trifluoromethyl) benzoic (Compound dd34) in place of 4 - [[(3R) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] pyrrolidin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b 1 1).
LCMS: m / z 580 [M + H] + HPLC retention time: 0.60 min (condition of F analysis) [Example 634] Compound n 13 A / -r3-f4-ff2-chloro-4-f (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-6- (trifluoromethyl) phenylmethylpiperazin-1-yl-3-oxopropylcarbamate ferric-butyl The title compound was synthesized from 3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide (Compound D-1 ) under the same conditions as for Compound DD-1. However, 3 - [(2-methylpropan-2-yl) oxycarbonylamino] propanoic acid was used in place of 1 H-pyrrole-2-carboxylic acid, and HATU was used instead of HBTU.
[Example 635] Compound N- 12 4-r [4- (3-aminopropanompiperazin-1-inmetin-3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyH-5- (trifluoromethyl-P-benzamide The title compound was synthesized from h / - [3- [4 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperazine- Feryl-butyl 1-yl] -3-oxopropyl] carbamate (Compound n13) under the same conditions as for Compound DD-62.
LCMS: m / z 609 [M + H] + HPLC retention time: 0.48 min (analysis condition A) [Example 636] Compound N- 13 3-chloro - / \ n (5-chloro-2-ethylsulfonyl-phenethyl-4- [r4- (piperidine-4-carbonyl) -piperazin-1-inmethyl-5- (trifluoromethyl) -benzamide The title compound was synthesized from 3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-methylmethyl) -5- (trifluoromethyl) benzamide (Compound D- 1) under the same conditions as for Compounds n13 and N-12. However, under the conditions of Compound n13, 1 - [(2- methylpropan-2-yl) oxycarbonyl] piperidine-4-carboxylic acid in place of 3 - [(2-methyl-p-n-2-yl) oxycarbonyl] propanic acid.
LCMS: m / z 649 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 637] Compound N- 14 3-chloro- / V-f (5-chloro-2-ethylsulfonylphenimmetin-4- [f4 - [(3R) -pyrrolidine-3-carboniHpiperazin-1 -i P metH H-5- (triflu promised Dbenzam ida The title compound was synthesized from 3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide (Compound D-1 ) under the same conditions as for Compounds n 13 and N-12. However, under the conditions of Compound n 13, (3R) -1 - [(2-methylpropan-2-yl) oxycarbonyl] pyrrolidine-3-carboxylic acid was used in place of 3 - [(2-methylpropan-2 -yl) oxycarbonylamino] propanoic.
LCMS: m / z 635 [M + H] + H PLC retention time: 0.52 min (analysis condition A) [Example 638] Compound n14 / N / -f2-f4-fr2-chloro-4-f (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-6- (trifluoromethylphenylmethylpiperazin-1-yl-butyl yl-ethylletylcarbamate) The title compound was synthesized from 3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4- (piperazin-1-ylmethyl) -5- (trifluoromethyl) benzamide (Compound D-1 ) under the same conditions as for Compound H-5. However, the reaction was performed by using ferric butyl A / - (2-bromoethyl) carbamate instead of ethyl iodide and with the addition of TEA.
[Example 639] Compound N- 15 4-rf4- (2-aminoetiPpiperazin-1-inmethyl-3-chloro- (5-chloro-2- Ethyl sulfonylphenimethyl-5- (trifluoromethylbenzamide) The title compound was synthesized from N- [2- [4 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperazin [Beta] -ethyl] ethyl] tert-butyl carbamate (Compound n14) under the same conditions as for the Compound B-1 LCMS: m / z 581 [M + H] + HPLC retention time: 0.44 min (condition of F analysis) [Example 640] Compound N- 16 3-chloro-A / -f (5-chloro-2-ethylsulfonylphenyl) metill-4-ff (3S) -3- (methylsulfamoylamino) pyrrolidin-1 -M1metn-5- (trifluoromethylbenzamide) The title compound was synthesized from 4 - [[(3S) -3-aminopyrrolidin-1-yl] methyl] -3-chloro - / [- [(5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benza ida (Compound DD-55) under the same conditions as for Compound DD-58.
LCMS: m / z 631 [M + H] + H PLC retention time: 0.53 min (analysis condition F) [Example 641] Compound N-17 3-chloro- / V-f (5-chloro-2-ethylsulfonylphenyl) metin-4-rr (3S) -3- (propan-2-ylamino) pyrrolidin-1-methane-5- (trifluoromethyl) benzamide The title compound was synthesized from 4 - [[(3S) -3-aminopyrrolidin-1-yl] methyl] -3-chloro - / [- [(5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benzamide (Compound DD-55) under the same conditions as for Compound B-3. However, MeOH was used in place of THF as a reaction solvent.
LCMS: m / z 580 [M + H] + H PLC retention time: 0.55 min (F analysis condition) [Example 642] Compound N-18 3-bromo- / V-f (5-chloro-2-ethylsulfonylphenol) metin-4-rf (3R) -3- (methylsulphamoxylamino) pyrrolidin-1 -nmethyl-5- (trifluoromethyl) benzamide The title compound was synthesized from 4 - [[(3R) -3-aminopyrrolidin-1-yl] methyl] -3-bromo- / [- ((5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benzamide (Compound E-2) under the same conditions as for Compound DD-58 LCMS: m / z 675 [M + H] + HPLC retention time: 0.54 min (condition of F analysis) [Example 643] Compound N-19 3-chloro-A / -r (5-chloro-2-ethylsulphonylphenyl) methan-4-rf (3S) -3- (cyclobutylaminolpiperidin-l-2-methyl-5- (trifluoromethylbenzamide The title compound was synthesized from 4 - [[(3S) -3-aminopiperidin-1-yl] methyl] -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound D-18) under the same conditions as for Compound DD-28. However, cyclobutanone was used in place of 3-oxetanone as the solvent.
LCMS: m / z 606 [M + H] + HPLC retention time: 0.61 min (condition of F analysis) [Example 644] Compound N 15 / V-r (3S) -1-fr2-chloro-4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-1-6- (trifluoromethyl) phenylmethylpiperidin-3-yl-1-A / -2- [methyl-r (2- Butyl methylpropan-2-ylcarbonylamino-1-ylmethylcarbamate The title compound was synthesized from 4- (bromomethyl) -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd16) under the same conditions as for Compound dd 17. However, / V-methyl-A / - [2 - [(2-methylpropan-2-yl) oxycarbonyl - [(3S) -piperiin-3-yl] amino] ethyl] was used. Ferric butyl carbamate in place of N- [2 - [[(3S) -piperidin-3-yl] sulfamoyl] ethyl] carbamic acid ester.
[Example 645] Compound N-20 3-chloro-V-r (5-chloro-2-ethylsulfonyl-phenylemin-4-yr (3S) -3-r2- (methylamino) ethylaminolpipperidin-1-inmetin-5- (trifluoromethyl-benzamide The title compound was synthesized from N - [(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin- 3-yl] - / S / - [2- [Methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] ethyl] ferba-butyl carbamate (Compound N 15) under the same conditions as for Compound B-1.
LCMS: m / z 609 [M + H] + HPLC retention time: 0.46 min (condition of F analysis) [Example 646] Compound N-21 4-ff -3- (3-aminopropinpiperidin-1-inmetill-3-chloro- (5-chloro- 2-Ethylsulfonylphenimetin-5- (trifluoromethyl) benzamide The title compound was synthesized from 4- (bromomethyl) -3-chloro - / [- [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd 16) under the same conditions as for Compounds n 15 and N-20. However, under the conditions of Compound N 15, A / - [3 - [(3R) -piperidin-3-yl] propyl] carbamic acid was used in place of N-methyl- / V- [2- [(2-methylpropan-2-yl) oxycarbonyl - [(3S) -piperidin-3-yl] amino] ethyl] carbamic acid ester.
LCMS: m / z 594 [M + H] + HPLC retention time: 0.43 min (F analysis condition) [Example 647] Compound N 16 5-chloro-2-cyclopentylsulfanylbenzonitrile The title compound was synthesized from 5-chloro-2-fluorobenzonitrile under the same conditions as for Compound a 1. However, cyclopentantiol was used in place of ethanethiol.
[Example 648] Compound N 17 (5-chloro-2-cyclopentylsulfanylphenimethanamine) The title compound was synthesized from 5-chloro-2-cyclopentylsulfanylbenzonitrile (Compound N16) under the same conditions as for Compound a2.
[Example 649] Compound N 18 cyclopentylsulfonylphenmethanamine hydrochloride The title compound was synthesized from (5-chloro-2-cyclopentylsulfanylphenyl) methanamine (Compound No. 17) under the same conditions as for Compound a3.
[Example 650] Compound N 19 / V- 1 -rr2-chloro-4-ft5-chloro-2- cyclopentylsulfonylphenyl) methylcarbamom-6- (trifluoromethyl) pheninmethylpiperidin-3-yl-1-A / tert-butyl methylcarbamate The title compound was synthesized from (5-chloro-2-cyclopentylsulfonylphenyl) methanamine hydrochloride (Compound N18) under the same conditions as for Compound A-14. However, 3-chloro-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5- (trifluoromethyl) acid was used. ) benzoic (compound dd34) instead of 4-bromo-3-trifluoromethylbenzoic acid.
[Example 651] Compound N-22 3-Chloro-A / -r (5-Chloro-2-cyclopentylsulfonyl-phenylimine-4-rf (3S) -3- (methylamino) piperidin-1-immethyl-5- (trifluoromethyl) benzamide The title compound was synthesized from A / - [(3S) -1 - [[2-chloro-4 - [(5-chloro-2-cyclopentylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin -3-yl] - / - / - t-butyl methylcarbamate (Compound N 19) under the same conditions as for Compound B-1.
LCMS: m / z 606 [M + H] + H PLC retention time: 0.64 min (analysis condition F) [Example 652] Compounds N-23 and N-24 were synthesized from 4 - [(4-aminopiperidin-1-yl) methyl] -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5 - (trifluoromethyl) benzamide (Compound DD-61) under the same conditions as for Compound B-2. Compound N-23 3-Chloro-A / -r (5-Chloro-2-ethylsulfonyl-phenethyl-4-rr4- (dimethylamino) piperidin-1 -MI methyl-5- (triflu promised I) be nza mide LCMS: m / z 580 [M + H] + HPLC retention time: 0.46 min (analysis condition A) Compound N-24 1-rf2-Chloro-4-f (5-chloro-2-ethylsulfonyl) -methylcarbamoyl-6- (trifluoromethyl) phenylmethyl-N, N-dimethylpiperidine-4-amine oxide I LCMS: m / z 596 [M + H] H PLC retention time: 0.49 min (analysis condition A) [Example 653] Compound N20 15 (3S) -1-chloro-4-r (5-chloro-2-ethylsulfonylphenimethylcarbamom-6-) Ethyl (trifluoromethyl) phene-metho-piperidine-3-carboxylate 0 The title compound was synthesized from 3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl] -4-formyl-5- (trifluoromethyl) benzamide (Compound dd23) under the same conditions as for Compound b32. However, (3S) -piperidine-3 was used ethyl carboxylate in place of ferr-butyl A / - [[(2S) -pyrrolidin-2-yl] methyl] carbamate, and chloroform was used in place of THF as the solvent.
[Example 654] Compound N-25 Acid _ _ (3S) -1-rf2-chloro-4-f (5-chloro-2-ethylsulfonylphenol) methylcarbamom-6- (trifluoromethyl) phenyl-1-methyl-piperidine-3-carboxylic acid The title compound was synthesized from (3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-3-carboxylate of ethyl (Compound N20) under the same conditions as for Compound b8.
LCMS: m / z 581 [M + H] + HPLC retention time: 0.55 min (F analysis condition) [Example 655] Compound N-26 (3S) -1-f [2-chloro-4-r (5-chloro-2-ethylsulfonyl-phenyl) -methylcarbamom-6- (trifluoromethyl) -phiHmethyl-N. N -dimethylpiperidine-3-carboxamide H /, / V-dinnetamine (57 ml, 0.1 14 mmol) and DIPEA were added (36 mL, 0.206 mmol) to a solution of (3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine- 3-carboxylic acid (Compound N-25, 60 mg, 0.102 mmol) and HATU (51 mg, 0.134 mmol) in acetonitrile (1 mL), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by chromatography on an amino silica gel column (DCM / n-hexane) to yield the title compound (49 mg, 79%) as a colorless solid. .
LCMS: m / z 608 [M + H] + HPLC retention time: 0.52 min (analysis condition F) [Example 656] Compound N-27 (3S) -1 - R2-chloro-4-f (5-chloro-2-ethylsulfonyl-phenylmethylcarbamom-6- (trifluoromethyl) phenylHmetin-A / -methylpiperidine-3-carboxamide The title compound was synthesized from (3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-3- carboxylic (Compound N-25) under the same conditions as for Compound N-26. However, methanamine hydrochloride was used in place of N, N-dimethylamine.
LCMS: m / z 594 [M + H] + H PLC retention time: 0.52 min (F analysis condition) [Example 657] Compound N-28 (3S) -1 -ff2-chloro-4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamom-6- (trifluoromethyl) phenylHmetin-A / -r2- (dimethylamino) ethyl-piperidine-3-carboxamide The title compound was synthesized from (3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-3- carboxylic (Compound N-25) under the same conditions as for Compound N-26. However, h / ', L /' - dimethylethane-1, 2-diamine was used instead of N, / V-dimethylamine.
LCMS: m / z 651 [M + H] + HPLC retention time: 0.42 min (condition of F analysis) [Example 658] Compound N21 4-ff (3S) -1-rf2-chloro-4-f (5-chloro-2-ethylsulfonylphenyl) methylcarbamom-6- (trifluoromethylphenimethylpyridine-3-carbonylaminolpiperidine-1-tert-butylcarboxylate) The title compound was synthesized from (3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-3- carboxylic acid (Compound N-25) under the same conditions as for Compound N-26.
However, 4-aminopiperidine-1-tert-butyl carboxylate was used instead of / V, A / -dimethylamine.
[Example 659] Compound N-29 (3S) -1-fr2-chloro-4-r (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-6- (trifluoromethyl) phenyl-1-methyl-A / -piperidin-4-ylpiperidine-3-carboxamide The title compound was synthesized from 4 - [[(3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfoni, il) meti le rbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-3-carbonyl] amino] piperidine-1-carboxylic acid ester (Compound N21) under the same conditions as for Compound B-1.
LCMS: m / z 663 [M + H] + H PLC retention time: 0.42 min (F analysis condition) [Example 660] Compound o1 5-chloro-2-ethylsulfanil aniline synthesized the title compound from 2-amino-4-chlorobenzenethiol under the same conditions as for the Compound a4.
[Example 661] Compound o2 5-chloro-2-ethylsulfonylaniline The title compound was synthesized from 5-chloro-2-ethylsulfanylaniline (Compound or 1) under the same conditions as for Compound A-2 [Example 662] Compound o3 (5-chloro-2-ethylsulfonylphenhydrazine) The title compound was synthesized from 5-chloro-2-ethylsulfonylaniline (Compound o2) under the same conditions as for Compound a5.
[Example 663] Compound 0-1 (5-Chloro-2-ethylsulfonyl-phenin-2-phenyl-5- (trifluoromethyl-1,3-oxazole-4-carbohydrazide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) hydrazine (Compound o3) under the same conditions as for Compound A-14. However, 2-phenyl-5- (trifluoromethyl) -1,3-oxazole-4-carboxylic acid was used in place of 4-bromo-3- (trifluoromethyl) benzoic acid.
LCMS: m / z 474 [M + H] + H PLC retention time: 0.96 min (condition of F analysis [Example 664] Compound o4 1,2-dichloro-4-ethylsulfanyl-5-nitrobenzene intetizó the title compound from 1,2-dichloro-4-trobenzene under the same conditions as for the p a a 1. However, triethylamine was used in place of potassium carbonate.
[Example 665] Compound o5 4. 5-dichloro-2-ethylsulfanil aniline The title compound was synthesized from 1,2-dichloro-4-ethylsulfanyl-5-nitrobenzene (Compound o4) under the same conditions as for Compound f4. However, the reaction was performed by using ethanol instead of 2-propanol as a solvent and at a temperature of 80 ° C.
[Example 666] Compound 06 (4,5-dichloro-2-ethylsulfanylphenyl) hydrazine .
The title compound was synthesized from 4,5-dichloro-2-ethylsulfanylaniline (Compound o5) under the same conditions as for Compound a5.
[Example 667] Compound o7 3-chloro-N '- (4,5-dichloro-2-ethylsulfanylphenyl) -5- (t rifl u prometí libe nzoh id razid a The title compound was synthesized from (4,5-dichloro-2-ethylsulfanylphenyl) hydrazine (Compound 06) under the same conditions as for Compound A-1. However, 3-chloro-5- (trifluoromethyl) benzoic acid was used in place of 3-bromo-5- (trifluoromethyl) benzoic acid.
[Example 668] Compound 0-2 3-chloro-N '- (4,5-dichloro-2-ethylsulfonylphenyl) -5- (trifluoromethyl) benzohydrazide The title compound was synthesized from 3-chloro-N (4,5-dichloro-2-ethylsulfanylphenyl) -5- (trifluoromethyl) benzohydrazide (Compound o7) under the same conditions as for Compound A-2.
LCMS: m / z 475 [M + H] + H PLC retention time: 0.97 min (F analysis condition) [Example 669] Compound 08 3 i 4-ethylsulfanylbenzonitrile add sodium ethanethiolate (1.62 g, 19.27 mmol) to a solution of 3-amino-4-chlorobenzonitrile (1.96 g, 12.85 mmol) in DMF (12 mL), and stir at 80 ° C for 50 minutes when using a microwave reactor. The reaction solution was cooled to room temperature, and then diluted with EtOAc (250 mL). The resulting solution was washed with 13% saline (100 ml x 3), and the organic layer was then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography of amino (EtOAc / n-hexane) to produce the title compound (2.13 g, 93%) as a pale yellow solid.
LCMS: m / z 179 [M + H] + HPLC retention time: 2.00 min (analysis condition D) [Example 670] Compound 0-3 3-chloro-N, - (5-cyano-2-ethylsulfonylphenM) -5- (trifluoromethylbenzohydrazide Title compound from 3-amino-4-ethylsulfanylbenzonitrile (Compound 08) under the same conditions as for Compounds 06, 7 and 0-2. However, under the conditions of Compound 0-2, the reaction was carried out with the addition of THF.
LCMS: m / z 432 [M + H] + H PLC retention time: 0.85 min (analysis condition F) [Example 671] Compound o9 4-ethylsulfanyl-3-methylbenzonitrile synthesized the title compound from 4-fluoro-3-methylbenzonitrile under the same conditions as for the Compound a1.
[Example 672] Compound o10 4-Ethylsulfonyl-3-methylbenzonitrile synthesized the title compound from 4-ethylsulfate n-I-3-methylbenzonitrile (Compound o9) under the same conditions as for Compound A-2.
[Example 673] Compound o11 3 (b ethyl) -4-ethylsulfonylbenzonitrile synthesized the title compound from 4-ethylsulfonyl 3-methylbenzonitrile (Compound o10) under the same conditions as for Compound b6.
[Example 674] Compound o12 3- (aminomethyl) -4-ethylsulfonylbenzonitrile The title compound was synthesized from 3- (bromomethyl) -4-ethylsulfonylbenzonitrile (Compound 11) under the same conditions as for Compound bb9.
[Example 675] Compound 0-4 3-chloro-f (5-cyano-2-ethylsulfonylphenimetin-5-) (trifluoromethyl) benzamide The title compound was synthesized from 3- (aminomethyl) -4-ethylsulfonylbenzonitrile (Compound 12) under the same conditions as for Compound bb10. However, 3-chloro-5- (trifluoromethyl) benzoic acid was used in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1 -i Ijmeti l] -3- (trifluoromethyl) benzoic acid (Compound b3).
LCMS: m / z 431 [M + H] + HPLC retention time: 0.84 min (condition of F analysis) [Example 676] Compound o13 / V-f (tere-butyl 5-chloro-2-phenylsulfanylpheninemethylcarbamate) Boc20 (454 mg, 2.08 mmol) and TEA (483 mI, 3.48 mmol) were added to a solution of (5-chloro-2-fenilsulfanilfenil) methanamine (Compound dd39, 435 mg, 1 .74 mmol) in THF (17 mi ), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetate ethyl / hexane) to yield the title compound (510 mg, 84%). 1 H-RM N (300 MHz, CDCl 3) d: 7.17-7.42 (8H, m), 4.91 (1 H, brs), 4.39 (2H, d, J = 4.5 Hz), 1.44 (9H, s) .
[Example 677] Compound o14 (5-chloro-2-phenylsulfanylphenyl) methanamine hydrochloride i The title compound was synthesized from ferric butyl / [- ((5-chloro-2-phenylsulfanylphenyl) methyl] carbamate (Compound o13) under the same conditions as for Compound B-57. However, the reaction was carried out at a temperature of 40 ° C. [Example 678] Compound 0-5 3-chloro-A / -f (5-chloro-2-phenylsulfanyl-phenethyl-5- (trifluoromethyl) benzamide The title compound was synthesized from (5-chloro-2-phenylsulfanylphenyl) methanamine hydrochloride (Compound o14) under the same conditions as for Compound bb10. However, 3-chloro-5- (trifluoromethyl) benzoic acid was used in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- ( trifluoromethyl) benzoic acid (Compound b3).
LCMS: m / z 456 [M + H] HPLC retention time: 1.09 min (F analysis condition) [Example 679] Compound 0-6 N-rf2- (benzenesulfinyl) -5-chloropheninmethin-3-chloro-5- trifl or promethe hbenza mida M-CPBA (6.9 mg, 0.031 mmol) was added to a solution of 3-chloro- / V - [(5-chloro-2-phenylsulfanylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound 0-5, 47 mg, 0.10 mmol) in EtOAc (2 mL) under ice-cooling. After two hours, m-CPBA (6.9 mg, 0.031 mmol) was further added. Two hours later, m-CPBA (8.1 mg, 0.036 mmol) was added once again, and the mixture was stirred under ice-cooling for two hours. The reaction mixture was allowed to pass through an amino silica gel and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to produce the title compound (28 mg, 59%).
LCMS: m / z 472 [M + H] + HPLC retention time: 0.92 min (condition of F analysis) [Example 680] Compound o15 / N / -r2-ff 1 -ff2-chloro-4-f (5-chloro-2- Ethyl-sulfonyl-phenyl) -methylcarbamom-6- (trifluoromethyl) -phiHmethylpiperidine-3-carboninamino-ethyl- / / -methylcarbamate-ferric-butyl The title compound was synthesized from (3S) -1 - [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-3- carboxylic acid (Compound N-25) under the same conditions as for Compound N-26. However, A / - (2-aminoethyl) - A / - tert-butyl methylcarbamate was used instead of N, N-dimethylamine.
[Example 681] Compound 0-7 (3S) -1 -ff2-chloro-4-((5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-6- (trifluoromethyl) phenymethin-A / -r2- (methylamino) ethyllpiperidin-3-carboxamide The title compound was synthesized from N- [2 - [[(3S) -1 [[2-chloro-4 - [(5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidine-3-carbonyl] amino] ethyl] - / \ / - ferric butyl methylcarbamate (Compound o15) under the same conditions as for Compound B-1.
LCMS: m / z 637 [M + H] + H PLC retention time: 0.41 min (analysis condition F) [Example 682] Compound o16 4-r (2-benzhydryl-5-oxa-2,8-d, azaspiror3.51nonan-8-yl) methyH-3-chloro- / V-r (5-chloro-2-ethylsulfonylphenyl) metin-5- (trifluoromethyl) benzamide The title compound was synthesized from (4- (bromomethyl) -3-chloro - / [- [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd 16) under the Same conditions as for Compound g3, however, 2-benzhydryl-5-oxa-2,8-diazaspiro [3.5] nonane was used in place of piperazine-1-ferrobutylcarboxylate, and DIPEA was added. DMF instead of THF as a solvent.
[Example 683] Compound 0-8 3-chloro-AM (5-chloro-2-ethylsulfonylpheniOmetin-4- (5-oxa-2,8-diazaespi rof 3.51 nonan-8-ylmethyl) -5- (trifluoromethyl) benzamide 1-chloroethyl chloroformate (3.2 ml, 0.029 mol) was added to a solution of 4 - [(2-benzhydryl-5-oxa-2,8-diazaspiro [3.5] nonan-8-yl) methyl] -3-chloro -A / - [(5-Chloro-2-ethylsulfonylphenyl) methyl] -5-yl (trifluoromethyl) benzamide (Compound o16, 18 mg, 0.025 mmol) in DCM (2 mL), and was stirred at room temperature for 27 hours . 1-Chloroethyl chloroformate (1.6 mI, 0.015 mol) was further added to the reaction solution, and stirred at room temperature for 22 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with methanol (2 mL). The resulting solution was stirred under reflux for one hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (water / acetonitrile, 0.05% TFA) to yield the title compound (9 mg, 66%) as a colorless solid.
LC S: m / z 580 [M + H] + HPLC retention time: 0.57 min (condition of F analysis) 25 [Example 684] Compound P-1 A / '- (5-chloro-2-ethylsulfonylphenin-2-methyl-6-oxo-1 H-pyridine-4-carbohydrazide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) hydrazine (Compound o3) under the same conditions as for Compound A-14. However, 2-methyl-6-oxo-1 H-pyridine-4-carboxylic acid was used in place of 4-bromo-3- (trifluoromethyl) benzoic acid as a carboxylic acid.
LCMS: m / z 370 [M + H] + HPLC retention time: 0.50 min (analysis condition A) [Example 685] Compound p1 5-vodo-3- (trifluoromethyl) -1 H-pyridin-2-one The title compound was synthesized from 3- (trifluoromethyl) -l H-pyridin-2-one under the same conditions as for Compound N7. However, the reaction was carried out with the addition of potassium carbonate.
[Example 686] Compound p2 6-oxo-5- (trifluoromethyl-1 H-pyridine-3-carbonitrile The title compound was synthesized from 5-iodo-3- (trifluoromethyl) -l H-pyridin-2-one (Compound p 1) under the same conditions as for Compound m2.
[Example 687] Compound p3 6-oxo-5- (methyl trifluoromethyl-1 H-pyridine-3-carboxylate) The title compound was synthesized from 6-oxo-5- (trifluoromethyl) -lH-pyridine-3-carbonitrile (Compound p2) under the same conditions as for Compound m3.
[Example 688] Compound p4 6-Oxo-5- (trifluoromethyl-1 H -pyridine-3-carboxylic acid The title compound was synthesized from methyl 6-oxo-5- (trifluoromethyl) -1H-pyridine-3-carboxylate (Compound p3) under the same conditions as for Compound b8. However, MeOH was used instead of EtOH as the solvent.
[Example 689] Compound P-2 N-r (5-chloro-2-ethylsulfonylphenimetin-6-oxo-5- (trifluoromethyl-1H-pyridine-3-carboxamide The title compound was synthesized from 5-chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, 6-oxo-5- (trifluoromethyl) -1H-pyridine-3-carboxylic acid (Compound p4) was used in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl]] piperazin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3) as a carboxylic acid.
LCMS: m / z 423 [M + H] + HPLC retention time: 0.59 min (analysis condition A) [Example 690] Compound p5 / V-r (tere-butyl 5-chloro-2-ethylsulfanylphenimethylcarbamate) The title compound was synthesized from (5-chloro-2-ethylsulfanylphenyl-methanamine (Compound a2) under the same conditions as for Compound o15.
[Example 691] Compound p6 (5-Chloro-2-ethylsulfanylphenemethanamine hydrochloride) The title compound was synthesized from urea-butyl / N / - [(5-chloro-2-ethylsulfanylphenyl) methyl] carbamate (Compound p5) under the same conditions as for Compound B-57. However, the reaction was carried out at a temperature of 40 ° C.
[Example 692] Compound p7 3-chloro-A / -f (5-chloro-2-ethylsulfanylphenihmethyl-5- (t ifl) b ida The title compound was synthesized from (5-chloro-2-ethylsulfanylphenyl) methanamine hydrochloride (Compound p6) under the same conditions as for Compound bb10. However, 3-chloro-5- (trifluoromethyl) benzoic acid was used in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- ( trifluoromethyl) benzoic acid (Compound b3) as a carboxylic acid.
[Example 693] Compound P-3 3-chloro-AH (5-chloro-2-ethylsulfinylphenimethyl-5- (tri-fluo rom etihbenza mida The title compound was synthesized from 3-chloro - / [- [(5- chloro-2-ethylsulfanylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound p7) under the same conditions as for Compound 0-6.
LCMS: m / z 424 [M + H] + HPLC retention time: 0.82 min (condition of F analysis) [Example 694] Compound p8 3-ethylsulfanylpyridine-4-carbonitrile The title compound was synthesized from 3-chloropyridine-4-carbonitrile under the same conditions as for Compound a6. However, the reaction was carried out with the addition of potassium carbonate and at room temperature. [Example 695] Compound p9 (3-ethylsulfanylpyridin-4-inmethanamine) A solution of 2 M ammonia in methanol (1 mL) and 50% aqueous Rancy nickel suspension (1 mL) was added to a solution of 3-ethylsulfanylpyridine-4-carbonitrile (Compound p8, 82 mg, 0.5 mmol) in methanol. (10 ml), and stirred at room temperature for four hours under an atmosphere of hydrogen, followed by removal of the insoluble matter by filtration through celite, and then methanol was washed. The filtrate and washings were combined, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (66 mg, 80%) as a yellow oily substance.
H-NMR (300 MHz, CDCl 3) d: 8.51 (1 H, s), 8.43 (1 H, d, J 3. 6 Hz), 7.32 (1 H, d, J = 3.6 Hz), 3.95 (2H, s), 2.99 (2H, q, J = 5.4 Hz), 1.34 (3H, t, J = 5.4 Hz).
[Example 696] Compound p10 3-chloro - / \ M (3-ethylsulfanylpyrielin-4-yl) methy 11-5- (trifluoromethylbenzamide The title compound was synthesized from (3-ethylsulfanylpyridin-4-yl) methanamine (Compound p9) under the same conditions as for Compound bb10. However, 3-chloro-5- (trifluoromethyl) benzoic acid was used in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- ( trifluoromethyl) benzoic acid (Compound b3) as a carboxylic acid.
[Example 697] Compound P-4 3-chloro- / V-f (3-ethylsulfanylpyridin-4-ihmethyl-5- (trifluoromethyl) benzamide The title compound was synthesized from 3-chloro-A / - [(3-ethylsulfanylpyridin-4-yl) methyl] -5- (trifluoromethyl) benzamide (Compound p 10) under the same conditions as for the Compound A-2. However, the reaction was performed by using EtOAc instead of DCM as the solvent, and at a temperature of -20 ° C to 0 ° C.
LC S: m / z 407 [M + H] + HPLC retention time: 0.74 min (condition of F analysis) [Example 698] Compound p 1 1 2-ethylsulfanyl-5-methylbenzonitrile intetizó the title compound from 2-fluoro-5-nitrile under the same conditions as for the p or a1.
[Example 699] Compound p12 (2-ethylsulfanyl-5-methylphenyl) methanamine The title compound was synthesized from 2-ethylsulfanyl-5-methylbenzonitrile (Compound p1 1) under the same conditions as for Compound a2.
[Example 700] Compound r13 (2-Ethylsulfonyl 5-methylphenyl) methanamine hydrochloride The title compound was synthesized from (2-ethylsulfanyl-5-methylphenyl) methanamine (Compound p 12) under the same conditions as for Compound dd45.
[Ex 701] - - (trifluoromethyl-phenylmethylpiperidin-3-yl] -A-tert-butyl methylcarbamate The title compound was synthesized from (2-ethylsulfonyl-5-methylphenyl) methanamine hydrochloride (Compound p13) under the same conditions as for Compound bb10. However, 3-chloro-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -5- (trifluoromethyl) acid was used. ) benzoic acid (Compound dd34) instead of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3) as a carboxylic acid.
[Example 702] Compound P-5 3-Chloro-A / -f (2-ethylsulphonyl-5-nyrylphenimethyl-4-fr (3S) -3- (methylamino) piperdin-1-inmetin-5- (trifluoromethylbenzamide The title compound was synthesized from N- [. { 3S) -1 - [[2- Chloro-4 - [(2-ethylsulfonyl-5-methylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] piperidin-3-yl] - / / - methylcarbamate ter-te butyl (Compound p14) under the same conditions as for Compound B-57.
LCMS: m / z 546 [M + H] H PLC retention time: 0.54 min (analysis condition F) [Example 703] Compound P-6 A / '- (5-chloro-2-ethylsulfonylphenyl) -3- (trifluoromethyl) -1 H -pyrazole-4-carbohydrazide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) hydrazine (Compound o3) under the same conditions as for Compound A-14. However, 3- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid was used in place of 5-bromo-3- (trifluoromethyl) benzoic acid as a carboxylic acid.
LCMS: m / z 397 [M + H] + HPLC retention time: 0.65 min (condition of analysis F) [Example 704] Compound P-8 / V '- (5-chloro-2-ethylsulfonylphenyl) -2-ethyl-4-methyl-1 3-oxazole-5-carbohydrazide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) hydrazine (Compound o3) under the same conditions as for Compound A-14. However, 2-ethyl-4-methyl-1,3-oxazole-5-carboxylic acid was used in place of 4-bromo-3- (trifluoromethyl) benzoic acid as a carboxylic acid.
LCMS: m / z 372 [M + H] + HPLC retention time: 0.69 min (condition of F analysis) [Example 705] Compound p15 2-ff2-Chloro-4-f (tert-butyl 5-chloro-2-ethylsulfonylphenimethylcarbamoyl) -6- (trifluoromethyl) phenylmethyl-5-oxa-2,8- -8-carboxylate The title compound was synthesized from 4- (bromomethyl) -3-chloro - / [- [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd16) under the same conditions as for Compound dd 17. However, the reaction was performed using 5-oxa-2,8-diazaspiro [3.5] nonane-8-carboxylate of tere-butyl and DIPEA instead of h / - [2 - [(3S) -piperidin-3-yl] sulfamoyl] ethyl] tere-butyl carbamate and potassium carbonate, respectively, and at a temperature of 80 ° C. [Example 706] Compound P-9 3-chloro-A / -rt5-chloro-2-ethylsulfonyl-phenylethyl-4- (5-oxa-2,8-diazaspirof3.51nonan-2-ylmethyl) -5- (trifluoromethyl) benzamide The title compound was synthesized from 2 - [[2-chloro-4- [(5-Chloro-2-ethylsulfonylphenyl) methylcarbamoyl] -6- (trifluoromethyl) phenyl] methyl] -5-oxa-2, 8-diazaspiro [3.5] nonane-8-carboxylic acid ferric-butyl ester (Compound p15) under same conditions as for Compound B-1.
LCMS: m / z 580 [M + H] HPLC retention time: 0.45 min (condition of F analysis) [Example 707] Compound P-10 3-chloro-A / -r (5-chloro-2-ethylsulfonyl-phenethyl-4- (1,8-diazaspirof5.51undecan-8-methyl) -5- (trifluoromethylbenzamide The title compound was synthesized from 4- (bromomethyl) -3-chloro-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -5- (trifluoromethyl) benzamide (Compound dd 16) under the same conditions as for Compounds p15 and P-9. However, under the conditions of Compound p15, 1, 8-diazaspiro [5.5] undecane-1-fer-butylcarboxylate was used in place of 5-oxa-2,8-diazaspiro [3.5] nonane-8-carboxylate. tert-butyl.
LCMS: m / z 606 [M + H] HPLC retention time: 0.59 min (condition of F analysis [Example 708] Compound p16 1 - . 1-ethylsulfonylpyrrole-2-carbonitrile Ethanesulfonyl chloride (0.98 g, 7.60 mmol) was added to a mixed solution of 1 H-pyrrole-2-carbonitrile (500 mg, 5.43 mmol) and TEA (1.51 ml, 10.9 mmol) in TH F (5 ml). and DCM (5 ml), followed by stirring for three hours. A saturated aqueous solution of sodium chloride was added to the reaction mixture, followed by extraction with DCM. The organic layer was then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (694 mg, 69%) as a colorless oily substance.
LCMS: m / z 185 [M + H] + H PLC retention time: 0.55 min (analysis condition A) [Example 709] Compound p17 Tere-butyl V-f (1-ethylsulfonylpyrrol-2-yl) methylcarbamate Sodium borohydride (1.13 g, 29.8 mmol) was added in five portions at five minute intervals to a solution of 1-ethylsulfonylpyrrole-2-carbonitrile (Compound p16, 686 mg, 3.72 mmol), BOC20 (1.71 mL, 7.44 mmol) and nickel chloride hexahydrate (II) (221 mg, 0.93 mmol) in methanol (15 mL) while cooling to 0 ° C, and the mixture was kept at 0 ° C and stirred for one hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (629 mg, 59%) as a colorless solid.
LCMS: m / z 172 [M-Boc-NH2I + H PLC retention time: 0.72 min (analysis condition A) [Example 710] Compound p18 / \ M (3S) -1-rr2-chloro-4-r (1-ethylsulfonylpyrrol-2-yl) methylcarbamom-6- (trifluoromethyl) phenyl-3-methyl-3-in-tert-butyl-methylcarbamate The title compound was synthesized from ([beta] -butyl N - [(1-ethylsulfonylpyrrol-2-yl) methyl] carbamate (Compound p17) under the same conditions as for Compounds p6 and p7. reaction at room temperature under the conditions of p6, and 3-chloro-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-acid was used il] methyl] -5- (trifluoromethyl) benzoic (Compound dd34) in place of 3-chloro-5- (trifluoromethyl) benzoic acid under the conditions of p7. [Example 71 1] Compound P-1 1 3-chloro-A / -f (1-ethylsulfonylpyrrol-2-yl) methyH-4-fr (3S) -3- (methylamino) piperidin-l -i P met H-5- (t rif I uoro metí Dbenza mida The title compound was synthesized from A / - [(3S) -1 - [[2-chloro-4 - [(1-ethylsulfonylpyrrol-2-yl) methylcarbamoyl] -6- (trifl uo rom ethyl) phenyl] methyl] piperidin-3-yl] -A-tert-butyl methylcarbonate (Compound p18) under the same conditions as for Compound B-1.
LCMS: m / z 521 [M + H] + HPLC retention time: 0.55 min (analysis condition A) [Example 712] Compound p19 3-bromo-5-chloro-4-methyl benzoic acid The title compound was synthesized from 3-chloro-4-methylbenzoic acid under the same conditions as for Compound f9. However, the undiluted reaction was performed without using chloroform.
[Example 713] Compound p20 Ethyl 3-bromo-5-chloro-4-methylbenzoate The title compound was synthesized from 3-bromo-5-chloro-4-methylbenzoic acid (Compound p19) under the same conditions as for Compound b1.
[Example 714] Compound p21 Ethyl 3-chloro-5-cyano-4-methylbenzoate The title compound was synthesized from ethyl 3-bromo-5-chloro-4-methylbenzoate (Compound p20) under the same conditions as for Compound K-1. However, the reaction was carried out using NMP instead of DMF as a solvent, and at a temperature of 200 ° C.
[Example 715] Compound p22 Ethyl 4- (bromomethyl) -3-chloro-5-cyanobenzoate The title compound was synthesized from ethyl 3-chloro-5-cyano-4-methylbenzoate (Compound p21) under the same conditions as for Compound b6. However, the reaction was carried out at a temperature of 75 ° C.
[Example 716] Compound p23 3-chloro-5-cyano-4-f (ethyl 4-methylpiperazin-1-i P methybenzoate) The title compound was synthesized from 4- (bromomethyl) -3-chloro-5-cyanobenzoate (Compound p22) under the same conditions as for Compound g3. However, 1-methylpiperazine was used in place of piperazine-1-fer-butylcarboxylate.
[Example 717] Compound p24 3-cl or ro-5-cyano-4-f (4-methylpiperazin-1-i Dmetill benzoic acid The title compound was synthesized from ethyl 3-chloro-5-cyano-4 - [(4-methyl-piperazin-1-yl) methyl] benzoate (Compound p23) under the same conditions as for Compound b8. [Example 718] Compound P-12 3-chloro- / V - [(5-chloro-2-ethylsulfonylphenyl) methyl-1-5-cyano-4 - [(4-methyl-piperazin-1-di-methyl-benzamide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound bb10. However, 3-chloro-5-cyano-4 - [(4-methyl-piperazin-1-acid) was used il) methyl] benzoic acid (Compound p24) in place of 4 - [[4 - [(2-methylpropan-2-yl) oxycarbonyl] piperazin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b3) as a carboxylic acid.
LCMS: m / z 509 [M + H] + H PLC retention time: 0.51 min (analysis condition A) [Example 719] Compound q 1 4-chloropyridine-3-carbonitrile An aqueous solution of 48% tetrafluoroboric acid (10 mL) was added to a solution of 4-chloropyridin-3-amine (1.29 g, 10.0 mmol) in ethanol (10 mL) at 0 ° C. An aqueous solution (10 ml) of sodium nitrite (725 mg, 10.5 mmol) was added to the resulting mixed solution at the same temperature, and stirred at the same temperature for 30 minutes. The precipitate was collected by filtration and ethanol was washed, and the resulting brown solid (1.94 g) was then dissolved in acetonitrile (10 ml). A mixed solution of sodium cyanide (980 mg, 20.0 mmol) and copper cyanide (1) (896 mg, 10.0 mmol) in water (10 mL) and acetonitrile (1 mL) was added to the resulting solution at 0 ° C. , and stirred while gradually warming to room temperature for 10 hours. The reaction mixture was cooled to 0 ° C, after which a saturated aqueous solution of sodium bicarbonate was added, and it was stirred for five minutes. The resulting solution was extracted with ethyl acetate, and the organic layer was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (605 mg, 44%) as a pale yellow solid. 1 H NMR (300 MHz, CDCl 3) d: 8.87 (1 H, s), 8.72 (1 H, d, J = 3.9 Hz), 7.51 (1 H, d, J = 3.9 Hz).
[Example 720] C to q2 Nilpyridine-3-carbonitrile synthesized the title compound from 4-chloropyridine-3-carbonitrile (Compound q 1) under the same conditions as for Compound a1. However, sodium ethanethiolate was used in place of ethanethiol.
[Example 721] Compound q3 (4-ethylsulfanylpyridin-3-yl) methanamine , He synthesized the title compound from 4-ethylsulfanylpyridine-3-carbonitrile (Compound q2) under the same conditions as for Compound p9. However, the reaction was carried out at a temperature of 50 ° C.
[Example 722] Compound q4 3-chloro - / \ M (4-ethylsulfanylpyridin-3-yl) methy 11-5- (trifluoromethyl) benzamide The title compound was synthesized from (4-ethylsulfanylpyridin-3-yl) methanamine (Compound q3) under the same conditions as for Compound A-14. However, 3-chloro-5- (trifluoromethyl) benzoic acid was used in place of 4-bromo-3- (trifluoromethyl) benzoic acid, and dichloromethane was used as the solvent.
[Example 723] Compound Q-2 3-chloro-A / - [(4-ethylsulfonylpyridin-3-yl) methyl-1-5- (trifluoromethylbenzamide The title compound was synthesized from 3-chloro- / S / - [(4-ethylsulfanylpyridin-3-yl) methyl] -5- (trifluoromethyl) benzamide (Compound q4) under the same conditions as for Compound A-2. However, the reaction was performed using EtOAc as a solvent, and at a temperature of 0 ° C.
LCMS: m / z 407 [M + H] + HPLC retention time: 0.75 min (condition of F analysis) [Example 724] Compound q5 (1-Ethylsulfonylpyrrol-2-yl) methanamine hydrochloride tied the title compound from N - [(1-ethylsulfonylpyrrol-2-yl) methyl] carbamic acid ester (Compound p17) under the same conditions as for Compound B-57. [Example 725] Compound Q-9 N-f (1-ethylsulfonylpyrrol-2-ylmethyl-3- (trifluoromethyl) benzamide) The title compound was synthesized from (1-ethylsulfonylpyrrol-2-yl) methanamine hydrochloride (Compound q5) under the same conditions as for Compound A-14. However, 3- (trifluoromethyl) benzoic acid was used in place of 4-bromo-3- (trifluoromethyl) benzoic acid, and dichloromethane was used as the solvent.
LCMS: m / z 361 [M + H] + HPLC retention time: 0.80 min (analysis condition A) [Example 726] Compound q6 4-amino-AM (5-chloro-2-ethylsulfonylphenyl) metin-3-methoxybenzamide The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) methanamine hydrochloride (Compound a3) under the same conditions as for Compound A-21. However, 4-amino-3-methoxybenzoic acid was used in place of 3- (trifluoromethyl) benzoic acid.
[Example 727] Compound q7 4-f4-f (5-chloro-2-ethylsulfonylphenyl) methylcarbamoyl-2-methoxyanilinolpiperidine-1-butylcarboxylate Sodium triacetoxyborohydride (49.8 mg, 0.235 mmol) was added to a solution of 4-amino-A / - [(5-chloro-2-ethylsulfonylphenyl) methyl] -3-methoxybenzamide (Compound q6, 30.0 mg, 0.078 mmol) and Ferro-butyl 4-oxopiperidin-1-carboxylate (23.4 mg, 0.1 18 mmol) in chloroform (1 ml), and was stirred at room temperature for two hours. The reaction temperature was raised to 50 ° C, followed by two hours of further stirring. 4-Oxopiperidine-1-tert-butylcarboxylate (23.4 mg, 0.118 mmol) and sodium triacetoxyborohydride (49.8 mg, 0.235 mmol) were added, followed by 16 hours of further stirring. The reaction mixture was cooled to room temperature, followed by the addition of water and extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (28.0 mg, 63%) as a colorless solid.
LCMS: m / z 566 [M + H] + HPLC retention time: 0.89 min (condition of F analysis) [Example 728] Compound Q-10 N-r (5-chloro-2-ethylsulfonylphenimethyl-3-methoxy-4- (piperidin-4-ylamino-benzamide The title compound was synthesized from 4- [4 - [(5-chloro-2-ethylsulfonylphenol) methylcarbamoyl] -2-methoxyanilino] piperidine-1-carboxylate (Compound q7) under the same conditions as for Compound B-1.
LCMS: m / z 466 [M + H] + HPLC retention time: 0.47 min (condition of F analysis) [Example 729] C t 8 The title compound was synthesized from 4- amino-3-methoxybenzoic under the same conditions as for Compound dd5. However, the reaction was carried out at a temperature of 65 ° C.
[Example 730] Compound q9 4- (2-methoxy-4-methoxycarbonyl aniline) piperidine-1-tert-butylcarboxylate The title compound was synthesized from methyl 4-amino-3-methoxybenzoate (Compound q8) under the same conditions as for Compound q7.
[Example 731] Compound q 10 3-methoxy-4-rn-f (2-methylpropan-2-yl) oxycarboninpiperidin-4-ylamino-benzoic acid The title compound was synthesized from 4- (2-methoxy-4-methoxycarbonylanilino) piperidine-1-tert-butylcarboxylate (Compound q9) under the same conditions as for Compound b8. However, methanol was used as the solvent. [Example 732] Compound q 1 1 4-r4-r (5-Chloro-2-ethylsulfonylanilino) carbamom-2-methoxyanilinolpiperidine-1-butyl-butylcarboxylate The title compound was synthesized from (5-chloro-2-ethylsulfonylphenyl) hydrazine (Compound o3) under the same conditions as for Compound A-14. However, 3-methoxy-4 - [[1 - [(2-methylpropan-2-yl) oxycarbonyl] piperidin-4-yl-aminobenzoic acid (compound q 10) was used in place of 4-bromo-3- (trifluoromethyl) acid. )benzoic.
[Example 733] Compound Q-1 1 V '- (5-chloro-2-ethylsulfonylphenyl) -3-methoxy-4- (piperidin-4-ylamino) benzohydrazide hydrochloride TFA (0.4 ml) was added to a solution of 4- [4 - [(5-chloro-2-ethylsulfonylanilino) carbamoyl] -2-methoxyanilino] piperidine-1-ferrobutylcarboxylate (Compound q 1 1.35.9 mg, 0.063 mmol) in DCM (0.6 ml), and stirred at room temperature. After one hour, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (water / acetonitrile, 0.05% TFA). Fractions containing the substance of interest were collected and concentrated under reduced pressure, after which the resulting residue was dissolved by adding EtOH and a 1 N hydrochloric acid solution; and the resulting solution was concentrated under reduced pressure to yield the title compound (20.0 mg, 63%) as a colorless solid.
LCMS: m / z 467 [M + H] + H PLC retention time: 0.46 min (F analysis condition) [Example 734] C to q 12 Ithro-4- (trifluoromethoxy) benzene Ice (8 g) and sodium nitrite (378 mg, 5.48 mmol) were added to a mixture of 2-nitro-4- (trifluoromethoxy) aniline (1.1 g, 4.98 mmol), an aqueous solution of hydrochloric acid at room temperature. 35% (7.2 mi) and water (7.2 mi) under cooling with ice. After 20 minutes of stirring, acetic acid (5 ml) was added, and the mix at room temperature for 20 minutes. Sodium nitrite (80.7 mg, 1.17 mmol) was added, and the mixture was stirred for 20 minutes under ice-cooling, after which potassium iodide (1.22 g, 7.38 mmol) dissolved in 5 water was added. (1.5 mi), followed by 30 minutes of agitation. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed with a saturated aqueous solution of sodium thiosulfate, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (1.07 g, 65%) as an orange oily substance. 15 LCMS: m / z 334 [M + Hj * HPLC retention time: 0.90 min (condition of F analysis) [Example 735] Compound q 13 20 1-ethylsulfanyl-2-nitro-4- (trifluoromethoxy) benzene The title compound was synthesized from 1-iodo-2- Nitro-4- (trifluoromethoxy) benzene (Compound q12) under the same conditions as for Compound dd42. However, the reaction was carried out at 80 ° C.
[Example 736] Compound q 14 1 - . 1-Ethylsulfonyl-2-nitro-4- (trifluoromethoxybenzene The title compound was synthesized from 1-ethylsulfanyl-2-nitro-4- (trifluoromethoxy) benzene (Compound q13) under the same conditions as for Compound A-2. However, ethyl acetate was used in place of dichloromethane as the solvent. [Example 737] Compound q 15 2-ethylsulfonyl-5- (trifluoromethoxy) .aniline The title compound was synthesized from 1-ethyl Ifonyl-2-nitro-4- (trifluoromethoxy) benzene (Compound q 14) under the same conditions as for Compound f1 1. However, the reaction was carried out at room temperature when using a solvent mixed with acetic acid and methanol in place of a mixed solvent of a saturated aqueous solution of ammonium chloride and 2-propanol as solvent.
[Example 738] C t q 16 il-5- (trifluoromethoxy) phenylhydrazine The title compound was synthesized from 2-ethylsulfonyl-5- (trifluoromethoxy) aniline (Compound q 15) under the same conditions as for Compound a5.
[Example 739] Compound q 17 N- T (3S) -1 - ff4-fr2-ethylsulfonyl-5- (trifluoromethoxy) anilinolcarbamom-2- (trifluoromethyl-phenylmethylpiperidin-3-ill-A / tere-butyl methylcarbamate) The title compound was synthesized from [2-eti Isu Ifonyl-5- (trifluoromethoxy) phenyl] hydrazine (Compound q 16) under the same conditions as for Compound A-1. Nevertheless, 4 - [[(3S) -3- [Methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl] methyl] -3- (trifluoromethyl) benzoic acid (Compound b17) was used in place of 3-bromo-5- (trifluoromethyl) benzoic acid.
[Example 740] Compound Q-12 N'- -eti Hydrochloride Isu Ifoni 1-5- -4-rr (3S) -3- (methylamino) Diperidin-1 -illmethin-3- (trifluoromethylbenzoate) The title compound was synthesized from A / - [(3S) -1 - [[4 - [[2-ethylsulfonyl-5- (trifluoromethoxy) anilino] carbamoyl] -2- (trifluoromethyl) phenyl] methyl] piperidin- 3-yl] - / tert-butyl V-methylcarbamate (Compound q 17) under the same conditions as for Compound B-57.
LCMS: m / z 583 [M + H] + HPLC retention time: 0.56 min (condition of F analysis) [Example 741] Compound q18 / N / -f (3S) -1-r [4-rr2-ethylsulfanyl-5- (trifluoromethoxy) anilinocarbamoyl-2- (trifluoromethyl) nylmethyl] piperidin-3-in A / - ferric butyl methylcarbamate The title compound was synthesized from (1-ethyl) Ifanyl-2-nitro-4- (trifluoromethoxy) benzene (Compound q 13) under the same conditions as for Compounds q 15, q 16 and q 1 7. [Example 742 ] Compound Q-13 2. 2,2-trifluoroacetate of / V'-r2-ethylsulfanyl-5- (trifluoromethoxy) phenin-4-rf (3S) -3- (methylamino) piperidin-1-methylmethyl-3- (trifluoromethylbenzohydrazide The title compound was synthesized from A / - [(3S) -1 - [[4 - [[2-ethylsulfanyl-5- (trifluoromethoxy) anilino] carbamoyl] -2- (trifluoromethyl) phenyl] methyl] piperidin- 3-yl] - / tert-butyl V-methylcarbamate (Compound q18) under the same conditions as for Compound B-1.
LCMS: m / z 551 [M + H] + HPLC retention time: 0.62 min (condition of F analysis) [Example 743] Compound q 19 1,4-dichloro-2-methoxy-5-nitrobenzene Sulfuric acid (0.520 ml) and nitric acid (0.520 ml) were added to a mixture of 1,4-dichloro-2-methoxybenzene (1.01 g, 5.73 mmol) and sulfuric acid (0.235 ml) under cooling with ice, followed for four hours of agitation. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to yield the title compound (331 mg, 26%) as an orange solid.
LCMS: m / z 222 [M + H] + HPLC retention time: 0.83 min (condition of F analysis) [Example 744] Compound q20 1 - . 1-chloro-4-ethylsulfanyl-2-methoxy-5-nitrobenzene tetized the title compound from 1,4-dichloro-2- trobenzene (Compound q 19) under the same conditions as for Compound a 1.
[Example 745] Compound Q-14 3-chloro- / S /, - (5-Chloro-2-ethylsulphonyl-4-methoxyphenin-4-fr (3S) -3- (methylamino) pyridin-1-methylmethyl-5- (trifluoromethylbenzohydrazide The title compound was synthesized from 1-chloro-4-ethylsulfanyl-2-methoxy-5-nitrobenzene (Compound q20) under the same conditions as for Compounds q14, q15, q16, q17 and Q-12. However, under the conditions of Compound 17, 3-chloro-4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidin-1-yl was used ] methyl] -5- (trifluoromethyl) benzoic acid (Compound dd34) instead of 4 - [[(3S) -3- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amine] piperidin-1 -yl ] methyl] -3- (trifluoromethyl) benzoic acid (Compound b17).
LCMS: m / z 597 [M + H] + HPLC retention time: 0.54 min (condition of F analysis) [Example 746] Amina 1 / Tere-butyl V-methyl- / V-rf (2R) -pyrrolidin-2-ylmethylcarbamate A solution of tere-butyl / V - [[(2R) -pyrrolidin-2-yl] methyl] carbamate (302 mg, 1.46 mmol) and triethylamine (0.815 mL, 5.85 mmol) in DCM (3 mL) was cooled. mi) at 0 ° C, after which a solution of benzyl chloroformate (0.272 ml, 1.91 mmol) in DCM (1.5 ml) was added dropwise over five minutes, and the mixture was stirred at 0 ° C. ° C for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (2R) -2 - [[(2-methylpropan-2-yl) oxycarbonylamino] methyl] pyrrolidine-1-benzylcarboxylate (410 mg, 81%) as a colorless solid.
LCMS: m / z 335 [M + H] HPLC retention time: 0.83 min (analysis condition A) A solution of (2R) -2 - [[(2-methylpropan-2-yl) oxycarbonylamino] methyl] pyrrolidine-1-benzylcarboxylate (407 mg, 1.22 mmol) and methyl iodide (0.379 mL, 6.09 mmol) in DMF (2.4 ml) at 0 ° C, followed by the addition of sodium hydride (> 61% 5 oil, 96.5 mg, 2.45 mmol), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (2R) -2 - [[methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] methyl] pyrrolidine -1-benzylcarboxylate (414 mg, 97%) as a colorless oily substance.
LCMS: m / z 349 [M + H] + HPLC retention time: 0.90 min (analysis condition A) 0 10% palladium on carbon (43.5 mg) was added to a solution of (2R) -2 - [[methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] methyl] pyrrolidine-1-benzylcarboxylate (410 mg, 1.18 mmol) in MeOH (4.1 ml) under an argon atmosphere, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered of celite, and the filtrate was then concentrated under reduced pressure to yield the title compound (253 mg, quant.) as a colorless oily substance. 1 H NMR (270 MHz, CDCl 3) d: 2.73-3.51 (5H, m), 2.91 (3H, s), 1.26-1.99 (4H, m), 1.46 (9H, s).
[Example 747] Amina 2 / Tere-butyl V-methyl- / V-rf (2S) -pyrrolidin-2-immethylcarbamate The title compound was synthesized from tere-butyl A / - [[(2S) pyrrolidin-2-yl] methyl] carbamate under the same conditions as for A / -methyl- / V - [[(2R)] tere-butyl-pyrrolidin-2-yl] methyl] carbamate (Amin 1). 1 H NMR (270 MHz, CDCl 3) a: 2.76-3.46 (5H, m), 2.91 (3H, s), 1.26-1.97 (4H, m), 1.46 (9H, s).
[Example 748] Amina 3 A / -methyl-A / -rf (3S) -piperidin-3-inmetincarbamate tere-butyl The title compound was synthesized from tere-butyl A / - [[(3S) -piperidin-3-yl] methyl] carbamate under the same conditions as for A / -methyl-A / - [[(2R) -pyrrolidin-2- il] methyl] carbamic acid-butyl ester (Amine 1) 1 H-RM N (400 MHz, CDCl 3) d: 2.74-3.28 (4H, m), 2.85 (3H, s), 2.50-2.63 (1 H, m), 2.23-2.41 (1H, m), 1.36- 1.86 (4H, m), 1.45 (9H, s), 1.00-1.19 (1H, m).
[Ex 749] The title compound was synthesized from urea-butyl / V - [(3S) -piperidin-3-yl] carbamate under the same conditions as for ferric-butyl A / -methyl- / V - [[(2R) -pyrrolidin-2-yl] methyl] carbamate (Amine 1). However, ethyl iodide was used in place of methyl iodide in the N-alkylation step.
H-NMR (400 MHz, CDCl 3, 60 ° C) d: 3.08-3.83 (5H, m), 2.87-2.98 (1 H, m), 2.50-2.62 (1 H, m), 1.59-1. 93 (4H, m), 1 .46 (9H, s), 1 .10 (3H, t, J = 7.04 Hz).
[Example 751] Amina 6 / V-methyl-AMr (2R) -piperidin-2-iHmethylcarbamate fer-butyl The title compound was synthesized from urea-butyl h / - [[(2R) -piperidin-2-yl] methyl] carbamate under the same conditions as for A / -methyl-A / - [[(2R) Ferric-butyl-pyrrolidin-2-yl] methyl] carbamate (Amin. 1). 1 H-NMR (400 MHz, CDCl 3, 60 ° C) d: 3.14-3.20 (1 H, m), 3.03-3.13 (2 H, m), 2.89 (3 H, s), 2.71 -2.80 (1 H, m ), 2.57-2.65 (1 H, m), 1.75-1.82 (1 H, m), 1.54-1.64 (2H, m), 1.46 (9H, s), 1.26-1.48 (3H, m). [Example 752] Amina 7 / N / -r2-r (3S) -piperidin-3-yl-xy-oxycarbamate benzyl A solution of (3S) -3-hydroxypiperidine-1-fer-butylcarboxylate (100 mg, 0.497 mmol) in THF (0.5 ml) was cooled to 0 ° C, followed by the addition of sodium hydride (> 60% oil, 23.0 mg, 0.600 mmol), and stirred for 10 minutes. Sodium hydride (> 60% oil, 24.0 mg, 0.626 mmol) and 2-bromoethanamine bromate (122 mg, 0.596 mmol) were added, and the mixture was stirred at room temperature for three days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of (3S) -3- (2-aminoethoxy) piperidine-1-fer-butylcarboxylate (124 mg) was obtained as a yellow oily substance by low concentration reduced pressure.
Benzyl chloroformate (0.140 ml, 0.827 mmol) was added to a mixed solution of the crude product of (3S) -3- (2-aminoethoxy) piperidine-1-fer-butyl carboxylate (124 mg) and sodium bicarbonate (99.0). mg, 1.18 mmol) in ethanol / water (1/1, 2 ml), and stirred at room temperature for 16 hours.
The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the agent was removed from dried by filtration, a crude product of (3S) -3- [2- (phenylmethoxycarbonylamino) ethoxy] piperidine-1-fer-butylcarboxylate (178 mg) was obtained as a yellow oily substance by concentration under reduced pressure.
A solution of 4N hydrochloric acid / ethyl acetate was added to the crude product of (3S) -3- [2- (phenylmethoxycarbonylamino) ethoxy] piperidine-1-tert-butylcarboxylate (178 mg), and stirred at room temperature for one hour. 1N hydrochloric acid was added to the reaction mixture, followed by washing with ethyl acetate. The aqueous layer was made basic with an aqueous solution of 1 N sodium hydroxide, followed by extraction with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the title compound (23 mg, three step yield: 16%) was obtained as a yellow oily substance by concentration under reduced pressure. 1 H-NMR (400 MHz, CDCl 3) d: 7.27-7.40 (5H, m), 5.53-5.65 (1 H, m), 5.10 (2H, s), 3.29-3.61 (4H, m), 2.65-3.05 (5H, m), 1 .69-1 .86 (2H, m), 1 .51 -1 .63 (1 H, m), 1 .37-1 .49 (1 H, m).
[Example 753] Amina 8 / V- (2-hydroxyethyl) -A / -r (3S) -piperidin-3-tert-butylcarbamate butyl A solution of ferc-butyl / V - [(3S) -piperidin-3-yl] carbamate (100 mg, 0.499 mmol) and triethylamine (0.104 mL, 0.749 mmol) in DCM (2.5 mL) at 0 ° was cooled. C, followed by the addition of benzyl chloroformate (0.101 ml, 0.599 mmol), and stirred for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3S) -3 - [(2-methylpropan-2-yl) oxycarbonylamino] piperidine-1-benzylcarboxylate (159 mg , 95%) as a colorless solid.
LCMS: m / z 335 [M + H] + HPLC retention time: 0.82 min (condition of F analysis) A solution of (3S) -3 - [(2-methylpropan-2-yl) oxycarbonylamino] piperidine-1-benzylcarboxylate (150 mg, 0.449 mmol) in DMF (0.9 ml) was cooled to 0 ° C, followed by addition of sodium hydride (> 60% oil, 26.9 mg, 0.673 mmol), and stirred for 15 minutes. 2-Bromoethoxymethylbenzene (0.213 ml, 1.35 mmol) was added, and the mixture was stirred at room temperature for two hours. Sodium hydride (> 60% oil, 27 mg, 0.675 mmol) was added, followed by two hours of additional stirring. Water was added to the reaction mixture, followed by extraction with a mixed solvent of ethyl acetate and hexane. The organic layer was washed three times with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3S) -3 - [(2-methylpropan-2-yl) oxycarbonyl- (2-phenylmethoxyethyl) amino] piperidine-1 -Benzyl carboxylate (123 mg, 58%) as a colorless oily substance.
LCMS: m / z 469 [M + H] + HPLC retention time: 1.05 min (analysis condition F) 10% palladium on charcoal (20 mg) was added to a solution of (3S) -3 - [(2-methylpropan-2-yl) oxycarbonyl- (2-methyl-methoxyethyl) amino] piperidine-1-benzylcarboxylate (123). mg, 0.262 mmol) in MeOH (1 mL) under an argon atmosphere, and stirred at room temperature for 16 hours under an atmosphere of hydrogen. The reaction mixture was filtered through celite, and a crude product of a mixture of Amines 8 and 9 (80 mg) was obtained as a yellow oily substance by concentrating the filtrate under reduced pressure.
[Ex 754] A solution of (3S) -3- (hydroxymethyl) piperidine-1-carboxylic acid-butyl ester (200 mg, 0.929 mmol) and triethylamine (0.646 mL, 4.64 mmol) in DCM (3 mL) was cooled to 0 ° C, and a solution of sulfur trioxide-pyridine complex (482 mg, 2.79 mmol) in DMSO (1.5 ml) was added dropwise, followed by one hour of stirring at 0 ° C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of (3S) -3- was obtained formylpiperidine-1-fer-butyl carboxylate (200 mg) as a yellow oily substance by concentration under reduced pressure.
(Carbomethoxymethylene) triphenylphosphorane (466 mg, 1.39 mmol) was added to a solution of the crude product of (3S) -3-formylpiperidine-1-fer-butylcarboxylate (198 mg) in toluene (4 ml), and stirred at 90 ° C for 16 hours. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3R) -3 - [(E) -3-methoxy-3-oxoprop- 1-ethyl] piperidine-1-fer-butylcarboxylate (242 mg, two-step yield: 97%) as a colorless oily substance. 1 H-NMR (400 MHz, CDCl 3) d: 6.85 (1 H, dd, J = 7.1, 15.9Hz), 5.86 (1 H, dd, J = 1.8, 15.9Hz), 3.95-4.04 (1H , m), 3.87-3.95 (1 H, m), 3.73 (3 H, s), 2.76-2.86 (1 H, m), 2.65-2.75 (1 H, m), 2.27-2.39 (1 H, m), 1 .83-1 .93 (1 H, m), 1 .62-1 .73 (1 H, m), 1 .28-1 .56 (2H, m), 1. 45 (9H, s). 10% palladium on carbon (25 mg) was added to a solution of (3R) -3 - [(E) -3-methoxy-3-oxoprop-1-yl] piperidine-1-fer-butylcarboxylate (242) mg, 0.899 mmol) in MeOH (4 mL) under an argon atmosphere, and the mixture was stirred at room temperature for 16 hours under an atmosphere of hydrogen. The reaction mixture was filtered through celite, and (3R) -3- (3-methoxy-3-oxopropyl) piperidine-1-fer-butylcarboxylate (222 mg, 91%) was obtained as a colorless oily substance concentrating the filtering at reduced pressure. 1 H-NMR (400 MHz, CDCl 3) d: 3.82-3.95 (2H, m), 3.66 (3H, s), 2.73-2.83 (1 H, m), 2.44-2.54 (1H, m), 2.31-2.38 ( 2H, m), 1.76-1.86 (1 H, m), 1.34-1.73 (5H, m), 1.45 (9H, s), 1.01-1.15 (1H, m).
A suspension of lithium aluminum hydride (31.9 mg, 0.840 mmol) in THF (0.8 ml) was cooled to 0 ° C, and a solution of (3R) -3- (3-methoxy-3-oxopropyl) piperidine was added. -1-tert-butylcarboxylate (152 mg, 0.560 mmol) in THF (2 mL) dropwise, followed by one hour of stirring at 0 ° C. Water and a 1N sodium hydroxide aqueous solution were sequentially added to the reaction mixture, followed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield ferric (3R) -3- (3-hydroxypropyl) piperidine-1-carboxylate. butyl (115 mg, 84%) as a colorless oily substance. 1 H-NMR (400 MHz, CDCl 3) d: 3.85-3.96 (2H, m), 3.61-3.68 (2H, m), 2.74-2.83 (1H, m), 2.45-2.53 (1H, m), 1.80- 1.87 (1H, m), 1.54-1.68 (3H, m), 1.36-1.50 (2H, m), 1.45 (9H, s), 1.19-1.36 (2H, m), 1.03-1.14 (1H, m) .
TFA (0.4 mL) was added to a solution of tere-butyl (3R) -3- (3-hydroxypropyl) piperidine-1-carboxylate (31.0 mg, 0.127 mmol) in DCM (0.6 mL), and stirred at room temperature. environment for one hour. A crude product of the TFA salt of the title compound (143 mg) was obtained as an oily substance of yellow color by concentrating the reaction mixture under reduced pressure. The crude product was dissolved in MeOH, and the TFA was removed by using an anion exchange resin (manufactured by Biotage Japan Ltd., MP-Carbonate). A crude product of the title compound (20 mg) was obtained as a yellow oily substance by concentrating the eluate under reduced pressure.
LCMS: m / z 144 [M + H] + [Example 755] Amina 1 1 A / -f2-f (3R) -piperidin-3-ylcarboxy benzyl ester An aqueous solution of 1 N sodium hydroxide (0.516 ml) was added to a solution of (3R) -3- (3-methoxy-3-oxopropyl) piperidine-1-ferrobutylcarboxylate (70.0 mg, 0.258 mmol ) in MeOH (2 mL), and stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed sequentially with a 1N hydrochloric acid solution and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of (3 - [(3R) -1 - [(2-methylpropan-2-yl) oxycarbonyl] piperidin-3-yl] propanoic acid was obtained. (66.1 mg) as a colorless solid by concentration under reduced pressure.
Diphenylphosphoryl azide (77.0 ml, 0.359 mmol) was added to a solution of the crude product of (3 - [(3R) -1 - [(2-methylpropan-2-yl) oxycarbonyl] piperidin-3-yl] propanoic acid (66.0 mg) ) and triethylamine (53.0 ml, 0.385 mmol) in toluene (1.3 ml), and stirred at 85 ° C for one hour. Benzyl alcohol (53.0 ml, 0.513 mmol) was added, and the mixture was further stirred at 85 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3R) -3- [2- (phenylmethoxycarbonylamino) ethyl] piperidine-1. -carboxylate of fer-butyl (84.0 mg) as a colorless solid.
TFA (0.4 mL) was added to a solution of (3R) -3- [2- (phenylmethoxycarbonylamino) ethyl] piperidine-1-tert-butylcarboxylate (84.0 mg) in DCM (0.6 mL), and stirred at room temperature. environment for one hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and a crude product of the title compound (43.0 mg) was obtained as a yellow oily substance by concentration under reduced pressure.
LCMS: m / z 263 [M + H] + HPLC retention time: 0.40 min (condition of F analysis) [Example 756] Amina 12 -3-ferro-butyl n-propycarbamate Diisopropyl azodicarboxylate (0.104 ml, 0.524 mmol) was added to a solution of (3R) -3- (3-hydroxypropyl) piperidine-1-fer-butylcarboxylate (85 mg, 0.349 mmol), triphenylphosphine (137 mg, 0.524). mmol) and phthalimide (77.0 mg, 0.524 mmol) in THF (1.7 mL), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3S) -3- [3- (1,3-dioxoisomol-2 -yl) propyl] piperidine-1-tert-butylcarboxylate (126 mg, 97%) as a yellow oily substance.
LCMS: m / z 373 [M + H] + HPLC retention time: 0.94 min (condition of F analysis) TFA (0.8 ml) was added to a solution of (3S) -3- [3- (1, 3-dioxoisoindol-2-yl) propyl] piperidine-1-ferrobutylcarboxylate (126 mg, 0.338 mmol) in DCM (1.2 ml), and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of 2- [3 - [(3R) -piperidin-3-yl] propyl] isomol-1,3-dione (78.0 mg) was obtained as an oily substance of yellow color by concentration under reduced pressure.
LCMS: m / z 273 [M + H] + HPLC retention time: 0.40 min (condition of F analysis) A solution of the crude product of 2- [3 - [(3R) -piperidin-3-yl] propyl] isoindol-1,3-dione (78.0 mg) and triethylamine (60.0 ml, 0.429 mmol) in DCM was cooled (1 .4 ml) at 0 ° C, and benzyl chloroformate (58.0 ml, 0.343 mmol) was added, followed by one hour of stirring at 0 ° C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3S) -3- [3- (1,3-dioxoisoindole-2- il) propyl] piperidine-1-benzylcarboxylate (65.0 mg, two-step yield: 42%) as a colorless oily substance.
LCMS: m / z 407 [M + H] + HPLC retention time: 0.93 min (condition of F analysis) Hydrazine monohydrate (80.0 mg, 1.60 mmol) was added to a solution of (3S) -3- [3- (1, 3-dioxoisomol-2-yl) propyl] piperidine-1-benzylcarboxylate (65.0 mg , 0.160 mmol) in EtOH (1.6 mL), and stirred at 60 ° C for one hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and water was added to the resulting residue, followed by three times by extraction with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of (3S) -3- (3-aminopropyl) piperidine-1-benzylcarboxylate (78.0 mg) was obtained as a yellow oily substance by concentration under reduced pressure. .
LCMS: m / z 277 [M + H] + HPLC retention time: 0.46 min (condition of F analysis) Boc20 (69.8 mg, 0.320 mmol) was added to a mixed solution of the crude product of (3S) -3- (3-aminopropyl) piperidine-1-benzylcarboxylate (44.2 mg) and sodium bicarbonate (53.8 mg, 0.640 mmol). ) in ethanol / water (1/1, 1 ml), and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated to about half its volume under reduced pressure, and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3S) -3- [3 - [(2-methylpropan-2-yl) oxycarbonylamino] propyl] piperidine-1-carboxylate of benzyl (39.0 mg, yield in two stages: 65%) as a colorless oily substance.
LCMS: m / z 377 [M + H] + H PLC retention time: 0.92 min (analysis condition F) 10% palladium on charcoal (10 mg) was added to a solution of (3S) -3- [3 - [(2-methylpropan-2-yl) oxycarbonylamino] propyl] piperidine-1-benzylcarboxylate (39.0 mg, 0.104 mmol) in MeOH (2 mL) under an argon atmosphere, and the mixture was stirred at room temperature for 16 hours under an atmosphere of hydrogen. The reaction mixture was filtered through celite, and a crude product of the title compound (23.0 mg) was obtained as a yellow oily substance by concentrating the filtrate under reduced pressure.
LCMS: m / z 243 [M + H] + [Example 757] Amina 13 tere-butyl TFA (2 mL) was added to a solution of (3S) -3 - [(2-methylpropan-2-yl) oxycarbonylamino] piperidine-1-benzylcarboxylate (364 mg, 1.09 mmol) in DCM (3 mL). ), and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of (3S) -3-aminopiperidine-1-benzylcarboxylate (302 mg) was obtained as a colorless oily substance by concentration under reduced pressure.
LCMS: m / z 235 [M + H] + H PLC retention time: 0.38 min (F analysis condition) 2- (1,3-Dioxoisomol-2-yl) ethanesulfonyl chloride (140 mg, 0.512 mmol) was added to a solution of the crude product of (3S) -3-aminopiperidine-1-benzylcarboxylate (100 mg) and DIPEA (0.149 mL, 0.854 mmol) in DCM (2 mL), and stirred at room temperature for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3S) -3- [2- (1,3-dioxoisomdol-2-yl) ethylsulfonyl] -lamino] piperidine - 1-benzylcarboxylate (213 mg) as a foamy yellow substance.
LC S: m / z 472 [M + H] + HPLC retention time: 0.75 min (condition of F analysis) Hydrazine monohydrate (214 mg, 4.27 mmol) was added to a solution of (3S) -3- [2- (1, 3-dioxoisoindol-2-l) ethylsulfonylamino] piperidine-1-benzylcarboxylate (201 mg, 0.427 mmol) in EtOH (3 mL), and stirred at 60 ° C for one hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and water was added to the resulting residue, followed by three times by extraction with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of (3S) -3- (2-aminoethylsulfonylamino) piperidine-1-benzylcarboxylate was obtained (168 mg) by concentration under reduced pressure.
LCMS: m / z 342 [M + H] + HPLC retention time: 0.43 min (F analysis condition) Boc20 (186 mg, 0.854 mmol) was added to a mixed solution of the crude product of (3S) -3- (2-aminoethylsulfonylamino) piperidine-1-benzylcarboxylate (146 mg) and sodium bicarbonate (143 mg, 1. 71 mmol) in ethanol / water (1/1, 2 ml), and stirred at room temperature for two hours. The reaction mixture was concentrated to about half its volume under reduced pressure, and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3S) -3- [2 - [(2-methylpropan-2-yl) oxycarbonylamino] ethylsulfonylamino] piperidine-1-carboxylate of benzyl (166 mg, two-step yield: 88%) as an oily yellow substance.
LCMS: m / z 442 [M + H] + HPLC retention time: 0.76 min (condition of F analysis) 10% palladium on charcoal (10 mg) was added to one Solution of (3S) -3- [2 - [(2-methylpropan-2-yl) oxycarbonylamino] ethylsulfonylamino] piperidine-1-benzylcarboxylate (92.0 mg, 0.208 mmol) in MeOH (2 mL) under an argon atmosphere , and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and a crude product of the title compound (65 mg) was obtained as a colorless oily substance by concentrating the filtrate under reduced pressure.
LCMS: m / z 308 [M + H] + [Example 758] Amina 14 2- (dimethylammon) -AM (3S) -piperidin-3-inetansulfonamide Paraformaldehyde (17.6 mg, 0.586 mmol) was added to a solution of (3S) -3- (2-aminoethylsulfonylamino) piperidine-1-benzylcarboxylate (50.0 mg, 0.146 mmol) in formic acid (1 ml), and stirred Mix at 80 ° C for four hours. Paraformaldehyde (17.6 mg, 0.586 mmol) was added additionally, and the mixture was stirred at 80 ° C for two more hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. This product was washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of chloride of sodium, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane) to produce (3S) -3- [2- (dimethylamino) ethylsulfonylamino] piperidine-1-benzylcarboxylate (27.7 mg, 51%) as a brown oily substance.
LCMS: m / z 370 [M + H] + HPLC retention time: 0.45 min (condition of F analysis) 10% palladium on charcoal (15 mg) was added to a solution of (3S) -3- [2- (dimethylamino) ethylsulfonylamino] piperidine-1-benzylcarboxylate (27.0 mg, 0.0731 mmol) in MeOH (2). mi) under an argon atmosphere, and the mixture was stirred at room temperature for 16 hours under an atmosphere of hydrogen. The reaction mixture was filtered through celite, and a crude product of the title compound (21 mg) was obtained as a yellow oily substance by concentrating the filtrate under reduced pressure.
LCMS: m / z 236 [M + H] + [Example 759] Amina 1 5 N-methyl-N- \ 2 - \ (2- ethyl ropan-2-yl) oxycarbonyl-f (3S) -piperidin-3-inaminoletylcarbamate ferric-butyl TFA (4 mL) was added to a solution of (3S) -3 - [(2-meti Ip clothing n-2-yl) oxycarbon i lam i] pi pe rid i na- 1-benzylcarboxylate (487 mg , 1.46 mmol) in DCM (6 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of (3S) -3-aminopiperidine-1-benzylcarboxylate was obtained by concentration under reduced pressure.
LCMS: m / z 235 [M + H] + H PLC retention time: 0.37 min (F analysis condition) Fer-butyl V-methyl- / V- (2-oxoethyl) carbamate was synthesized from A / - (2-hydroxyethyl) -A / -methylcarbamate using the method described in the literature (B100rganic and Medicinal Chemistry, vol 12, pp. 5147-5160, 2004).
A solution of the crude product of (3S) -3-aminopiperidine-1-benzylcarboxylate (107 mg) and / V-meti I -L / - (2 - oxoethyl) tere-butyl carbamate (59.3 mg, 0.343 mmol) in chloroform (2.1 ml) at 0 ° C, followed by the addition of sodium triacetoxyborohydride (145 mg, 0.685 mmol), and stirred at 0 ° C. After 30 minutes, N-me tere-butyl [2- (5-oxoethyl) carbamate tert -butyl (6.0 mg, 0.035 mmol) was added, and the mixture was stirred at 0 ° C for an additional 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, a crude product of (3S) -3- [2- [Methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] ethylamino] piperidine-1-carboxylate was obtained. benzyl (169 mg) as a yellow oily substance by concentration under reduced pressure.
LCMS 15: m / z 392 [M + H] + HPLC retention time: 0.51 min (condition of F analysis) Boc20 (188 mg, 0.863 mmol) was added to a solution of the crude product of (3S) -3- [2- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] ethylamino] piperidine-1 - benzyl carboxylate (169 mg) and triethylamine (0.180 ml, 1.30 mmol) in THF (2.2 ml), and the mixture was stirred at room temperature for three hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography. 25 silica gel (ethyl acetate / hexane) to produce (3S) -3- [2- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] ethyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] piperidine-1-benzylcarboxylate (139 mg, two-step yield: 62%) as an oily yellow substance.
LCMS: m / z 492 [M + H] + H PLC retention time: 1.04 min (F analysis condition) 10% palladium on charcoal (20.0 mg) was added to a solution of (3S) -3- [2- [methyl - [(2-methylpropan-2-yl) oxycarbonyl] amino] ethyl - [(2-methylpropan-2) -yl) oxycarbonyl] amino] piperidine-1-benzylcarboxylate (12 mg, 0.228 mmol) in MeOH (2.2 ml) under an argon atmosphere, and the mixture was stirred at room temperature for 16 hours under an atmosphere of hydrogen . The reaction mixture was filtered through celite, and a crude product of the title compound (12 mg) was obtained as a yellow oily substance by concentrating the filtrate under reduced pressure.
LCMS: m / z 358 [M + H] + [Example 760] Amine 16 / V-f2-ff (3S) -piperidine-3-carbonyl-amino-carbamate tere-butyl A solution of (3S) -1-phenylmethoxycarbonylpiperidine-3-carboxylic acid (72.0 mg, 0.273 mmol), tere-butyl A / - (2-aminoethyl) carbamate (52.6 mg, 0.328 mmol) and HBTU (124 mg) was cooled. , 0.328 mmol) in DCM (1.3 mL) at 0 ° C, followed by the addition of DIPEA (0.136 mL, 0.820 mmol), and was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to yield (3S) -3- [2 - [(2-methylpropan-2- yl) oxycarbonylamino] ethylcarbamoyl] piperidine-1-benzylcarboxylate (81.0 mg, 73%) as a colorless oily substance.
LCMS: m / z 406 [M + H] + H PLC retention time: 0.71 min (analysis condition F) 10% palladium on charcoal (15.0 mg) was added to a solution of (3S) -3- [2 - [(2-methylpropan-2-yl) oxycarbonylamino] ethylcarbamoyl] piperidine-1-benzylcarboxylate (81). .0 mg, 0.200 mmol) in MeOH (2.2 ml) under an argon atmosphere, and the mixture was stirred at room temperature for 16 hours under an atmosphere of hydrogen. The reaction mixture was filtered through celite, and a crude product of the title compound (58.0 mg) was obtained as a colorless solid by concentrating the filtrate under reduced pressure.
LCMS: m / z 272 [M + H] + Pharmacological study 1 . Measurement of adhesion activity of DDR1 The adhesion activity of DDR1 was measured through the Eu Kinase Union Test of LanthaScreen (manufactured by Life Technologies Corporation) (Registered Trade Mark). A test compound and a kinase tracer 178 labeled with 647 (manufactured by Life Technologies Corporation) of Alexa Fluor (Registered Trade Mark) was added to a mixture of DDR1 and Eu-anti-GST antibody from LanthaScreen (Registered Trade Mark). After the reaction at room temperature for one hour, the energy transfer was measured by fluorescence resonance. The 50% inhibitory concentration (Cl50) of the inhibition ratio was calculated relative to a control free of test compound. 2. Functional test of the DDR1 Path-Hunter The human osteosarcoma U20S cell line was suspended (manufactured by DiscoveRX Corporation) with overexpression of DDR1 and SHC1 in a medium (MEM Eagle Medium, manufactured by Life Technologies Corporation) supplemented with 10% fetal bovine serum and antibiotics (500 mg / ml Geneticin (G418): manufactured by Life Technologies Corporation and 250 pg / ml hygromycin) to prepare a cell suspension at a concentration of 10,000 cells / 100 ml. This cell suspension was added to a 96-well plate and the cells were cultured at 37 ° C in a 5% carbon dioxide incubator for one hour. Then the medium was removed after confirm that the cells adhered to the plate. A serial dilution of the test compound was performed with dimethylsulfoxide and then added to 50 ml of Cell Planting reagent 16 (manufactured by DiscoveRX Corporation) and the mixture was divided into aliquots 5 for the 96-well plate. After incubation at 37 ° C in the 5% carbon dioxide incubator for one hour, 50 ml of 100 mg / ml of collagen was provided for the tissue culture (Collagen Type lC, manufactured by Nitta Gelatin I nc.) and the plate was incubated at 37 ° C in the incubator of carbon dioxide at io 5% for 24 hours. The incubated plate was returned to normal temperature and was provided to the 25 ml plate of the prepared Path-Hunter Detection Kit (manufactured by DiscoveRX Corporation). The plate was incubated at normal temperature for two hours in the dark. The measurement was made at 1 sec / well using a fluorescence plate reader. The 50% inhibitory concentration (C 150) of the test compound was calculated from the value when the test compound was added relative to the control free of test compound.
The results are shown in Tables 14 to 24. 20 [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] 3. Measurement of the antitumor effect The antitumor effect was measured for the representative examples of the compounds of the present invention.
The anti-tumor effect was measured using cancer-bearing mice in which the endometrial human cancer cell line MFE-280 (manufactured by DSMZ) was subcutaneously transplanted into the groin of the BALB / c nude mouse (manufactured by Charles River Laboratories Japan, Inc. .).
Approximately 1 x 107 MFE-280 cells were transplanted subcutaneously into the groin of nude mice acquired after a one-week quarantine period. It was measured the size of the tumor with gauges, and the volume of the tumor was calculated (tumor volume = length x width2 / 2 (mm3)). The mice were subjected to the experiment when the tumor size was approximately 200 mm3.
The test compound was suspended in a solution for administration and 0.4 ml of the suspension was administered orally once a day. The antitumor effect was calculated as the inhibition of tumor growth by comparing the tumor growth between the drug treated group and the control group administered with solution on day 1 1 after the start of administration.
Inhibition of tumor volume growth (TGI) = (1 - growth of tumor volume in the group treated with the drug / growth of tumor volume in the control group) x 100 (%) The results are shown in Table 25 and Fig. 1 .
[Table 25] 4. Measurement of the inhibition of DDR1 phosphorylation in tumors The inhibition of DDR1 was measured by the compound of test on MFE-280 tumors using the Western-type transfer test.
Four hours after the final administration, the tumors were homogenized and solubilized, subjected to SDS-PAGE and then transferred to the PVDF membrane. After blocking, the membrane was treated with an antiphosphorylated Y796-DDR1 antibody (manufactured by Sigma-Aldrich Co. LLC), an anti-DDR1 antibody (manufactured by Santun Cruz Biotechnology, Inc.) and an anti-actin antibody (manufactured by Santun Cruz Biotechnology, Inc.). After washing the primary antibodies, the membrane was treated with a secondary antibody labeled with HRP. After washing, the signals were detected by a chemiluminescence method using ECL Plus or ECL (manufactured by GE Healthcare).
The results are shown in Fig. 2.
From these results, it was observed that the compounds of the present invention have high inhibitory activity of DDR1 and a high antitumor effect.
[Industrial Applicability] Compounds that have a DDR1 inhibitory effect are provided by the present invention. Also provided by the present invention are pharmaceutical products for the prevention and / or treatment of cancer, prevention and / or treatment of cancer invasion and metastasis and prevention and / or treatment of fibrosis and inflammation.

Claims (17)

  1. CLAIMS 1 . A compound represented by the following general formula (I): [where Q represents CH2 or NH; Ring A represents formula (1) or (2) below: R4 / ".N JT (2) where A represents N or CR1; R1 represents a halogen atom, cyano group, alkyl group of 1 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms, where the alkyl group of 1 to 3 carbon atoms and the alkoxy group of 1 to 3 atoms of carbon can be substituted with 1 to 5 halogen atoms; R1 can be a hydrogen atom when A2 and / or A3 are N; A2 represents N or CR2; R 2 represents a hydrogen atom, halogen atom, alkyl group of 1 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms, where the alkyl group of 1 to 3 carbon atoms and the alkoxy group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms; A3 represents N or CR3; R3 represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 3 carbon atoms or an alkoxy group of 1 to 3 carbon atoms, wherein the alkyl group of 1 to 3 carbon atoms and the alkoxy group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms; Y R4 represents an alkylsulfonyl group of 1 to 6 carbon atoms, alkylsulfanyl group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, cycloalkylsulfonyl group of 3 to 8 carbon atoms, cycloalkylsulfanyl group of 3 to 8 atoms carbon, cycloalkylsulphinyl group of 3 to 8 carbon atoms, arylsulfonyl group of 6 to 10 carbon atoms, arylsulfanyl group of 6 to 10 carbon atoms or arylsulfinyl group of 6 to 10 carbon atoms; Y Ring B represents any of the following formulas (3) to (9): where B1 represents N or CH; B2 represents N or CR5; R5 represents a halogen atom, alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkenyl group of 2 to 6 carbon atoms, cyano group, group nitro, cycloalkyl group of 3 to 8 carbon atoms, aromatic ring of 4 to 10 members, aromatic heterocycle of 4 to 10 members, heterocycle of 3 to 12 members or alkylsulfanyl group of 1 to 6 carbon atoms, wherein the alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkenyl group of 2 to 9 carbon atoms or alkylsulfanyl group of 1 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms; B3 represents N or CR6; B6 represents O, S or NR6; R6 represents a hydrogen atom, the alkyl group of 1 to 3 carbon atoms optionally substituted with a hydroxyl group, halogen atom, amino group, OCOCH3 group or group represented by the following formula (i): · - X-Y- Z (i) where in the formula (i), X represents - (CH2) n-, -N H- or -O-; Y represents a cycloalkyl group of 3 to 8 carbon atoms, aromatic ring of 4 to 10 members, heterocycle of 3 to 12 members, aromatic heterocycle of 4 to 10 members or - (NH (CH2) q) r-, wherein the cycloalkyl group of 3 to 8 carbon atoms, aromatic ring of 4 to 10 members, heterocycle of 3 to 12 members or aromatic heterocycle of 4 to 10 members can be substituted with 1 to 5 alkyl groups of 1 to 6 carbon atoms; Z represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, dimethylamine oxide, - (CH2) mNRaRb, -NRiCOCH2Rc, - (CH2) mN RiCORc, - (CH2) mORd, - (CH2) mCORe, - (CH2) mNRjS02Rk, - (CH2) mS02Rk, - (CH2) mCONRIRrn, cycloalkyl group of 3 to 8 carbon atoms, aromatic heterocycle of 4 to 10 members or heterocycle of 3 to 12 members, where the aromatic heterocycle of 4 to 10 members or 3 to 12 membered heterocycle can be substituted with 1 to 5 alkyl groups of 1 to 6 carbon atoms; n represents 0, 1, 2 or 3; m represents 0, 1, 2 or 3; q represents 0, 1, 2 or 3; r represents 0, 1, 2 or 3; Ra and Rb are identical or different, each represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, an alkyl group of 2 to 6 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, a heterocycle of 3 to 12 members or -S02CH3, wherein the alkyl group of 1 to 6 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, heterocycle of 3 to 12 members or alkynyl group of 2 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms, hydroxyl groups, alkoxy groups of 1 to 6 carbon atoms, amino groups, -CONH2, mono-alkylamine of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms, cyano groups, OCH2Ph and / or heterocycle of 3 to 12 members; Re represents an alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, hydroxyl group, cyano group, 3 to 12 membered heterocycle, aromatic heterocycle of 4 to 10 members or 5 amino group, wherein the alkyl group of 1 to 6 carbon atoms can be independently substituted with 1 to 3 hydroxyl, amino, mono-alkylamino of 1 to 6 carbon atoms and / or di-alkylamino of 1 to 6 carbon atoms; Rd represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, where the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 3 hydroxyl and / or amino groups; Re represents an alkyl group of 1 to 6 carbon atoms, hydroxyl group, 3 to 12 membered heterocycle or aromatic heterocycle of 4 to 10 members, wherein the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 3 hydroxyl and / or amino groups; Ri represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, wherein the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms; Rj represents a hydrogen atom or alkyl group of 1 to 6 carbon atoms, where the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms; Rk represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, amino group, mono-alkylamino group of 1 to 6 carbon atoms or di-alkylamino group of 1 to 6 carbon atoms, wherein the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 3 hydroxyl, amino, mono-alkylamino of 1 to 6 carbon atoms and / or di-alkylamino of 1 to 6 carbon atoms; Y R1 and Rm are identical or different, each represents a hydrogen atom, alkyl group of 1 to 6 carbon atoms or heterocycle of 3 to 12 members, wherein the alkyl group of 1 to 6 carbon atoms can be independently substituted with 1 at 3 amino, mono-alkylamino of 1 to 6 carbon atoms and / or di-alkylamino of 1 to 6 carbon atoms; B4 represents N or CR7; R7 represents a hydrogen atom, halogen atom, cyano group, alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkenyl group of 2 to 6 carbon atoms or cycloalkyl group of 3 to 6 carbon atoms (where the alkyl group of 1 to 6 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkenyl group of 2 to 6 carbon atoms or cycloalkyl group of 3 to 8 carbon atoms can be substituted with 1 to 5 halogen atoms) or a group represented by the following formula (ii): · - X2-Y2-Z2 (i) where X2 represents - (CH2) P-; p represents 0, 1, 2 or 3; Y2 represents an aromatic ring of 4 to 10 members, 3 to 12 membered heterocycle or 4 to 10 membered aromatic heterocycle wherein the 4- to 10 membered aromatic ring, 3 to 12 membered heterocycle or 4 to 10 membered aromatic heterocycle can be substituted with 1 to 5 1 to 5 alkyl groups at 6 5 carbon atoms; Z2 represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, hydroxyl group, -NRfRg, 3- to 12-membered heterocycle or 4- to 10-membered aromatic heterocycle, wherein the alkyl group of 1 to 6 carbon atoms it may be substituted with 1 to 5 halogen atoms and the 3- to 12-membered heterocycle or 4- to 10-membered aromatic heterocycle may be substituted with 1 to 5 alkyl groups of 1 to 6 carbon atoms; Y Rf and Rg are identical or different, each represents a hydrogen atom, alkyl group of 1 to 6 carbon atoms, -COCH3 or -SO2CH3; B5 represents N or CR8; Y R8 represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or halogen atom, where the alkyl group of 1 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms], a pharmaceutically acceptable salt thereof or its solvate. 2. The compound or a pharmaceutically acceptable salt 25 thereof according to claim 1, wherein the compound is represented by the following general formula (I I): [where Q, R1, R2, R3, R4, R5, R6, B4 and R8 as defined in claim 1, respectively] 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Q is CH2. 4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, where R2 represents a hydrogen atom or alkyl group of 1 to 3 carbon atoms, wherein the alkyl group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms. 5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, where R3 represents a hydrogen atom, chlorine atom or alkyl group of 1 to 3 carbon atoms, where the alkyl group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms. 6. The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 5, wherein R5 represents a halogen atom, alkyl group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms, carbon or alkoxy group of 1 to 3 carbon atoms, where the alkyl group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms or alkoxy group of 1 to 3 carbon atoms can be substituted with 1 to 5 halogen atoms. 7. The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 6, wherein R6 represents a hydrogen atom or a group represented by the following formula (i): · - X- Y- Z (i) where X represents CH2; Y represents piperazine, pyrrolidine, piperidine, morpholine, 3,3-dimethylpiperazine, 3,6-diazabicyclo [3, 1, 1] heptane, azaspiro [2,4] heptane, 2-oxo-1,3-diazinano, 1, 2,5-oxadiazepane, 2-oxopiperidine, azetidine, 5-oxa-2,8-diazaspiro [3,5] nonane, 1,8-diazaspiro [5,5] undecane, imidazole or benzene; Z represents a hydrogen atom, - (CH2) mNRaRb, -N HCO C H2RC, - (CH2) mNHCORc, - (CH2) mORd, - (CH2) mCORe, - (CH2) mCONRIRm, piperazine, pyrrolidine, piperidine or tetrahydropyran; m represents 0, 1, 2 or 3; Ra and Rb are identical or different, each represents a hydrogen atom, alkyl group of 1 to 6 carbon atoms, cycloalkyl group of 3 to 6 carbon atoms or -S02CH3, where the alkyl group of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms can be substituted with 1 to 5 halogen atoms, hydroxyl groups, alkoxy groups of 1 to 6 carbon atoms, amino groups, -CONH2, mono-alkylamino of 1 to 6 carbon atoms, di-alkylamino of 1 to 6 carbon atoms or cyano groups; Re represents an alkyl group of 1 to 4 carbon atoms, alkoxy group of 1 to 4 carbon atoms, heterocycle of 4 to 6 members, aromatic heterocycle of 4 to 6 members or amino group, where the alkyl group of 1 to 4 atoms carbon can be independently substituted with 1 to 2 amino, mono-alkylamino of 1 to 2 carbon atoms and / or di-alkylamino of 1 to 2 carbon atoms; Rd represents a hydrogen atom or alkyl group of 1 to 2 carbon atoms, wherein the alkyl group of 1 to 2 carbon atoms can be substituted with an amino group or hydroxyl group; Re represents an alkyl group of 1 to 2 carbon atoms or a heterocycle of 4 to 6 members, wherein the alkyl group of 1 to 2 carbon atoms can be substituted with an amino group or hydroxyl group; Y R1 and R1 are identical or different, each represents a hydrogen atom, alkyl group of 1 to 3 carbon atoms or heterocycle of 4 to 6 members, where the alkyl group of 1 to 3 carbon atoms is substituted separately with 1 at 3 amino, mono-alkylamino of 1 to 3 carbon atoms and / or di-alkylamino from 1 to 3 carbon atoms. 8. The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 7, wherein 5 B4 represents CR7 and R7 represents a chlorine atom, bromine atom, hydrogen atom, cyano group, alkyl group of 1 to 3 carbon atoms, alkoxy group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms, cycloalkyl group from 3 to 6 carbon atoms (where the alkyl group of 1 to 3 carbon atoms, alkoxy group of 1 to 3 carbon atoms, alkenyl group of 2 to 3 carbon atoms or cycloalkyl group of 3 to 6 carbon atoms can be substituted with 1 to 3 halogen atoms) or group represented by the following formula (ii): 15 · - X2-Y2-Z2 (i i) where X2 represents - (CH2) P-, p represents 0 or 1; Y 2 represents piperazine, pyrrolidine, piperidine, morpholine or 3,3-dimethylpiperazine; Z2 represents a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, -NRfRg, pyrrolidine, morpholine or tetrahydropyran, where the alkyl group of 1 to 3 carbon atoms can be substituted with 1 to 3 halogen atoms; Y Rf and Rg are identical or different, each represents a hydrogen atom, alkyl group of 1 to 3 carbon atoms, 25 -. 25 -COCHs or -SO2CH3. 9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R8 represents a hydrogen atom. 10. A pharmaceutical product comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 as an active ingredient. eleven . The pharmaceutical products according to claim 10, wherein the pharmaceutical products are used for the treatment of cancer and / or carcinogenic invasion / metastasis. 12. The pharmaceutical products according to claim 10, wherein the pharmaceutical products are used for the treatment of fibrosis and / or inflammation. 13. A method for the treatment of cancer and / or cancerigenic invasion / metastasis, which comprises administering a therapeutically effective amount of a composition comprising the compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 9 to a patient in need of the same. 14. A method for the treatment of fibrosis and / or inflammation, comprising administering a therapeutically effective amount of a composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 to a patient in need of it. 15. The use of the compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 9 for the manufacture of an agent for the treatment of cancer and / or carcinogenic invasion / metastasis. 16. The use of the compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 9 for the manufacture of an agent for the treatment of fibrosis and / or inflammation. 17. The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 9 for use in the treatment of cancer and / or carcinogenic invasion / metastasis. The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 9 for use in the treatment of fibrosis and / or inflammation.
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